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IMMUNOLOGY 7105306 Part-9 Capture of Microbes by Antigen-Presenting Cells and Cell-Mediated Immune Responses References: Immunology , David Male et al 8th ed 2013 Basic Immunology , Abul K. Abbas and Andrew H. Lichtman, 3ed, 2011 Instructor: Dr Alaeddin Abuzant, PhD Microbiology and Immunology Email: [email protected] Microbes usually enter the body through the skin, the gastrointestinal tract (by ingestion), and the respiratory tract (by inhalation). (Some insect-borne microbes may be injected into the bloodstream as a result of insect bites.) All of the interfaces between the body and the external environment are lined by continuous epithelia. The epithelia and subepithelial tissues contain a network of dendritic cells(the same cells are present in the T cell zones areas of peripheral lymphoid organs) . These dendritic cells, are phagocytic cells. They belong to innate immune cells and play a major role in linking innate to adaptive immune response In the skin, the epidermal dendritic cells are called Langerhans cells. . Epithelial dendritic cells are said to be “immature,” . However, they are vey good in phagocytosis of microbes and damages cells They are called immature because they are inefficient YET to stimulate T lymphocytes activation The immature dendritic cells express membrane receptors (Pattern recognition receptors( PRR) by which that recognize microbes and damaged cells . Dendritic Cell Activation: Microbes can activate dendritic cells by binding to PRR such as Toll-like receptors (TLRs) by generating activating signals using their cytoplasmic ITIM motifs. PRR such as TLR receptors are also found on resident macrophages found in tissue. These microbes can detected by macrophage Toll like receptors leading for phagocytosis and production of inflammatory cytokine s such tumor necrosis factor (TNF) and interleukin-1 (IL-1). They cytokines can also activate near by Denritic cells So, dendritic cells can be activated by: by their TLR signaling and by inflammatory cytokines released by local macrophages at infection site Activation of Dendritic cells results several changes in their phenotype and function. Activated Dendritic Cells: They become more rounded ( lose their dendrites) Become less phagocytic and lose their adhesiveness for epithelia and begin to express CCR7 chemokine receptor that is specific for chemo attracting cytokines (chemokines) produced in the T cell zones of lymph nodes. These chemokines direct the dendritic cells to exit the epithelium and migrate through lymphatic vessels to the lymph nodes draining that epithelium During the process of migration, the dendritic cells mature from cells designed to capture microbes into APCs that are capable of activating T lymphocytes. This maturation of dendritic cells is reflected in: 1- Increased synthesis and stable expression of MHC molecules, which display antigen to T cells, 2- Expression of co-stimulatory molecules that are required for full T cell responses (B & needed for the second signals) 3- Production of cytokines that play role in T cell differentiation Notes: Soluble microbial antigens in the lymph are picked up by dendritic cells that reside in the lymph nodes Blood-borne microbes and microbial antigens are handled in essentially the same way by dendritic cells in the spleen. Recall that naive T lymphocytes continuously re-circulate through lymph nodes and also express CCR7 chemokine receptor , which promotes their entry into the T cell zones of lymph nodes in response to chemokines released from T cells zones. Therefore, dendritic cells bearing captured microbes or microbial antigen and naive T cells come together in lymph nodes. This process is remarkably efficient; it is estimated that if microbes or microbial antigens are introduced at any site in the body, a T cell response to these antigens begins in the lymph nodes draining that site within 12 to 18 hours ( or at MALT). ***The capture and presentation of protein antigens by dendritic cells. Immunol Lett. 2006 Apr 15;104(1-2) Expression and role of Fc- and complement-receptors on human dendritic cells. Bajtay Z1, Csomor E, Sándor N, Erdei A. Abstract Dendritic cells (DCs) are professional antigen presenting cells, which take up pathogens/foreign structures in peripheral tissues, then migrate to secondary lymphoid organs where they initiate adaptive immune responses by activating naive T-cells. In the early phase of antigen uptake pattern recognition receptors (including mannose-, scavenger- and toll-like receptors) that recognize pathogen-associated molecular patterns play an important role. Later receptors binding opsonized antigen are also involved in phagocytosis. These cell membrane molecules include various Fc-receptors, recognizing different isotypes of antibodies and various complement-receptors, such as CR3, CR4 and the C1q-binding complex of calreticulin and CD91. Different types of APCs Serve distinct functions in T cell– dependent immune responses. The type of activated dendritic cells influence the nature of T cell differentiation ( mainly CD4 T cells) Various subsets of dendritic cells can direct the differentiation of naïve CD4+ T cells into distinct populations ( TH1, TH2, Th17 and regulatory CD4 T cells) that function in defense against different types of microbes . Differention of CD4 T cells into different types of effector CD4 T cells is mediated by the cytokines they were exposed to during the activation process Cross-Presentation initiating the responses of CD8+ T lymphocytes to the antigens of intracellular microbes The immune system, and especially CD8+ T lymphocytes, must be able to recognize and respond to the antigens of these intracellular microbes. However, viruses may infect any type of host cells. These infected cells may not produce all of the signals that are needed to initiate T cell activation. How, then, are naive CD8+ T lymphocytes able to respond to the intracellular microbes? A likely mechanism is that dendritic cells ingest infected cells and display the antigens present in the infected cells for recognition by CD8+ T lymphocytes This process is called cross-presentation (or cross-priming), to indicate that one cell type, the dendritic cells, can present the antigens of other cells, the infected cells, and prime (or activate) naive T lymphocytes specific for these antigens. The dendritic cells that ingest infected cells may also present microbial antigens to CD4+ helper T lymphocytes. Thus, both classes of T lymphocytes, CD4+ and CD8+ cells, specific for the same microbe are activated close to one another. This process may be important for the antigen-stimulated differentiation of naive CD8+ T cells to effector CTLs, which in some cases require help from effector CD4+ cells. Part-II Cell-Mediated Immune Responses There are two types of intracellular infections during which microbes survive within cells: and require cell mediated immunity: First: microbes are ingested by phagocytes as part of the early defense mechanisms of innate immunity, but some of these microbes have evolved to resist the microbicidal activities of phagocytes and instead of being killed, these microbes survive and replicate within the phagocytes. Second: viruses bind to receptors on a wide variety of cells and are able to infect and replicate in the cytoplasm of these cells. These cells often do not possess intrinsic mechanisms for destroying the viruses. ( Recall that cells infected with viruses produce alpha interferones as a very early defense step against viral infection. Alpha interferones may interfere with viral replication, however, they do not always succeed) The arm of the adaptive immune response whose role is to combat/fight infections by intracellular microbes is represented by T lymphocytes, and is known as cell mediated adaptive immune response that include CD4 and CD8 T cells. Recall that, CD4+ helper T lymphocytes also help B cells to produce antibodies. Although antibodies are important when dealing with extracellular microbes or toxins, some times antibodies play an important role in destroying infected cells by the process (ADCC) mediated by NK cells and macrophages Activation of T lymphocytes: Activation of Naive T cells involves three major steps: 1. Recognition of major histocompatibility complex (MHC)- displaying microbial peptide antigens on antigen-presenting cells (DCs) 2. Recognition of co-stimulatory molecules on DCs( B7) 3. Exposure to cytokines ( these cytokines are produced by DC, other cells, or by activated T cells them selves) ( T cell activation requires several TCR engaged to several MHC. This lead to receptor aggregation that is important for triggering of activation signals . Activation signals are triggered by TCR complex, CD co-receptor, and CD28) Triggering of activation signals result in the following events in Naïve T cells: 1- Activation of surface adhesion molecules( integrines) that increase binding of naïve T cells to DCs ( this is important for T cell activation) 2- Expression of CD40 Ligand, which binds to CD40 on DC ( this will enhance the activation process by increasing the expression of B-7 on DC. This will increase the second signal triggered by CD28 molecules expressed on T cells) 3- Production cytokines, such as IL-2 as well as completing the expression of IL-2 receptor on the T cells being activated This leads to an autocrine effect of IL-2 that results in proliferation of activated T cells (clonal expansion) 4- Differentiate of activated T cells into: 1. Effector cells, which serve various functions in cell-mediated immunity 2. Memory cells, which survive for long periods. Phases of T Cell Activation Antigen Recognition by naïve T cells , Co-stimulation of T cell b y B-7, and Exposure to cytokines results in the following: 1. The TCR recognizes MHC-associated peptide antigens---activation signal 1 2. CD4 or CD8 co-receptors recognize the MHC molecules---activation signal 1 3. Signal 1 causes activation of adhesion molecules LFA-1 that strengthen the binding of T cells to DCs ( activated LFA-1on T cells binds to ICAM-1 on DCs) (Note: activation of LFA-1 on T cells is triggered by signals from TCR or a chemokine receptor) 1. Receptors for co-stimulators such as CD28 on T cells recognize co-stimulatory molecules on activated DCs ( B7-1 and B7-2). This causes CD28 to trigger the signal 2 needed for T cell activation ----activation signal 2 5. First and second signals induce expression of CD40 ligand (CD40L) on T cells being activated. CD40 L binds to CD40 on DCs ( this will enhance the activation process by increasing the expression of B-7 on DC----Increase the second signal triggered by CD28 as more and more CD28 on T cells being activated bind to B 7 on DCs (Amplification of the second signal) 6. The first signal with amplified second signal induce the production of IL-2 by T cells being activated. In addition, these signals will induce the completion of IL-2 receptor on the T cells being activated . (IL-2 produced by T cells being activated binds to the completed IL-2 receptor on the same cells to exert an autocrine effect that triggers T cell proliferation (clonal expansion) 7. Exposure of activate T cells to cytokines from DCs ( or other cells) play a major role in T cell differentiation into effector T cells and memory T cells IMPORTANT NOTE: CD4 +T cells differentiation into TH1 Th2 Th17, Th19 and regulatory CD4 T cells is determined by the types of cytokines they are exposed to during the activation process /which can also be determined by the type of DC Accessory Molecules of T lymphocytes Involved in the Activation Process The molecules other than antigen receptors that are involved in T cell responses to antigens are called accessory molecules of T lymphocytes Accessory molecules are invariant ( conserved) among all T cells. Their functions fall into two categories: 1- Signaling molecules such as CD3 and ζ chain CD4/CD8 (first signal) and CD28 ( second signal) 2- Adhesion integrins such as LFA-1 T cell Activation: Two or more TCR complexes together with their co-receptors are needed to be engaged simultaneously with several MHC (harbor foreign peptide) to initiate the T cell response. This is because only when multiple TCRs and co-receptors are brought together an appropriate biochemical signaling cascades is triggered In addition, each T cell needs to engage antigen (i.e., MHC-peptide complexes) for a long period, at least for several minutes, or multiple times to generate enough biochemical signals to initiate a response. This can be mediated by adhesion molecules on T cells such as LFA-1 that bind to ICAM-1 on DC. On Naïve T cells, LFA-1 has a low affinity conformation. The first signal triggered by the TC complex induce conformational changes in LFA-1 in such a way that LFA-1 will have a high affinity for ICAM-1 Expressed on DCs . Specific T cell Activation: The biochemical Signals That Lead to T cell Activation In lymphocytes, two types of functions ( antigen recognition and signaling) are segregated into different sets of molecules. The TCR and BCR recognizes antigens, but it is not able to transmit biochemical signals to the interior of the cell. The TCR is non-covalently associated with a complex of proteins that are involved in signaling: CD3 and the ζ chain. (The TCR, CD3, and ζ chain make up the TCR complex). Other molecules involved in triggering signaling that is involved in T cells activation includes: CD4/CD8 co-receptors upon becoming bind to MHCI/MHCII respectively CD28 which binds to B-7 co-stimulatory molecules on DCs NON SPSECIFIC ACTIVATION OF T CELLS T cells can also be activated experimentally by molecules that bind to the TCRs of many or all clones of T cells, regardless of the peptide-MHC specificity of the TCR. These polyclonal activators of T cells include 1. Antibodies specific for the TCR or associated CD3 proteins 2. Polymeric carbohydrate-binding proteins such as phytohemagglutinin 3. Certain microbial proteins called superantigens. (Microbial super-antigens may cause serious disease by inducing excessive cytokine release from many T cells.)(the mediate non-specific binding of TCRs with MHC-II molecules) Polyclonal activators often are used as experimental tools to study T cell responses and in clinical settings to test for T cell function or to prepare metaphase spreads for chromosomal analyses. ROLE OF ADHESION MOLECULES IN T CELL RESPONSES Adhesion molecules on T cells recognize their ligands on DC and stabilize the binding of the T cells to the DCs. Most TCRs bind the peptide- MHC complexes for which they are specific with low affinity. To induce a productive response, the binding of T cells to DCs must be stabilized for a sufficiently long period that the necessary signaling threshold is achieved. This stabilization function is performed by adhesion molecules on the T cells LFA-1 ( whose ligands are expressed on DCs (ICAM-1) The most important of these adhesion molecules belong to the family of proteins called integrins. The major T cell integrin involved in binding to DCs during the activation process is the Leukocyte function–associated antigen-1 (LFA-1), whose ligand on DCs is called intercellular adhesion molecule-1 (ICAM-1). Source of signaling involved in Co-nversion of LFA-1 integrin from low affinity to high affinity: On resting naive T cells, the LFA-1 integrin is in a low-affinity state. But during T cell activation 1- Antigen recognition by a T cell: signaling from TCR complex causes LFA-1 on naive cells to convert to its high affinity state . As a result, T cells bind strongly to APCs providing a positive feedback loop 2- If a T cell is exposed to chemokines produced as part of the innate immune response to infection. Chemokine receptor on T cells initiate a signal that convert LFA-1 molecules to a high-affinity state. T cells bind strongly to APCs ( this usually happens at infection sites, such as infected macrophages) Note: Integrins also play an important role in directing the migration of effector T cells from the circulation to sites of infection. ROLE OF CO-STIMULATION IN T CELL ACTIVATION The full activation of T cells is dependent on the recognition of co-stimulators on DCs “second signals” for T cell activation A- B7-1 (CD80) and B7-2 (CD86) Both of which are expressed on DCs and whose expression is greatly increased when the APCs encounter microbes and/ or exposed to cytokines . B7 proteins are recognized by a receptor called CD28, which is expressed on virtually all naïve T cells. Signals from CD28 on T cells binding to B7 on APCs work together with signals generated by binding of the TCR and co-receptor to peptide-MHC complexes on the same APCs that activate T cells . B- CD40 ligand: First and second signals induce the expesstion of CD40 L on T cells being activated CD40L is expressed on an antigen- stimulated T cells CD40 L binds to CD40 on DCs This will activates the DCs to express more and more B7 co-stimulators and may also start secreting cytokines, This will enhance T cell activation (amplification of the second signal) Important Note: The requirement for co-stimulation ensures that naive T lymphocytes are activated fully by microbial antigens, and not by harmless foreign substances, because, as stated previously, microbes stimulate the expression of B7 co-stimulators on APCs If a naïve T cells recognize a peptide antigen on APC with high affinity in the absence of costimulation, this results in inactivation of these T cells ( Anergy/Peripheral tolerance) Practical Importance of Co-Stimulators on APCs Protein antigens, such as those used in vaccines, fail to elicit T cell–dependent immune responses unless these antigens are administered with substances that activate APCs, including dendritic cells and macrophages (and possibly B cells as well). Such substances are called adjuvants, and they function mainly by inducing the expression of co-stimulators on APCs and by stimulating the APCs to secrete cytokines that activate T cells. Enhancing the expression of co-stimulators may be useful for stimulating T cell responses (e.g., against tumors) Blocking co-stimulators may be a strategy for inhibiting unwanted responses. Agents that block B7:CD28 interaction are used in the treatment of rheumatoid arthritis and other inflammatory diseases, Antibodies to block CD40:CD40L interactions are being tested in inflammatory diseases and in transplant recipients to reduce or prevent graft rejection. Inhibitory Proteins Receptors Homologous to CD28 Are Critical for Limiting and Terminating Immune Responses. The prototypes of the inhibitory receptors are 1. CTLA-4, which, like CD28, recognizes B7 on APCs to give an inhibitory signal 2. PD-1, which recognizes different but related ligands on many cell types. Once PD-1 binds to its ligand, it triggers an inhibitory signal Both CTLA-4 and PD-1 are induced on activated T cells. The importance of these molecules appeared in certain situations such as: Genetic deletion of these molecules in mice results in excessive lymphocyte expansion and autoimmune disease CTLA-4 also is involved in inhibiting responses to some tumors PD-1 inhibits responses to some infections and allows the infections to become chronic. Many fundamental questions about when these inhibitory pathways become active, how the choice between activation and inhibition is determined, and how these inhibitory receptors work to shut off lymphocytes, remain to be answered.???????????????????? STIMULI FOR THE ACTIVATION OF CD8+ T CELLS The activation of CD8+ T cells starts with recognition of class I MHC–associated peptides on APCs. However, completion of the activation process requires: 1- Co-stimulation by B-7 expressed on DC ( as in the case of CD4 T cell activation) and / or 2- Cytokines from helper CD4 T cells that concomitantly activated along with CD8 T cells CD8 activation may require the concomitant activation of CD4+ helper T cells. When virus-infected cells are ingested by host dendritic cells and the viral antigens are cross-presented by the DCs, the same DC may present antigens on both MHC I and MHC II Thus, both CD8+ T cells and CD4+ T cells specific for viral antigens are activated near one another. The CD4+ T cells may produce cytokines or membrane molecules that help to activate CD8+ T cells. Cross-presentation: CD8 activation needs help from CD4+ effector T cells CD8 activation DOES NOT need help from CD4+ effector T cells Why HIV infected patients fail to mount an immune response involving CD8 T cells activation against MANY viral infections? Severe decrease in the number of helper CD4+ T cells killed by HIV virus in AIDS patients adversely affect CD8 activation in response to many viral infections Note: responses to SOME viruses do not appear to require help from CD4+ T cells, for reasons that are not known. Functional Responses of T Lymphocytes to Antigen and Co-Stimulation The recognition of antigen and co-stimulators molecules (B7) by T cells LEAD TO a set of responses that results in: A. Clonal expansion of activated T cells ( proliferation) B. Differentiation of the naive T cells into effector cells and memory cells During the process of T cells activation, T cells undergo several changes. Some of these changes are mediated by cytokines that are produced by T cells themselves during their activation. These cytokines can act on the T cells themselves ( autocrine effect). In addition, these cytokines may affect many other cells involved in immune defenses ( Paracrine effect) Phases of T Cell Responses SECRETION OF CYTOKINES AND EXPRESSION OF CYTOKINE RECEPTORS BY ACTIVATED T CELLS In response to recognition of both the peptide antigen and co-stimulators (B7), T lymphocytes, especially CD4+ T cells, rapidly secrete several different types of cytokines that have diverse activities The first cytokine to be produced by CD4+ T cells, within 1 to 2 hours during the activation process, is IL-2. The high-affinity receptor for IL-2 is a three chain molecule. However, Naive T cells express two signaling chains of this receptor but do not express the chain that enables the receptor to bind IL-2 with high affinity. Within 2 hours after the initiation of activation process, the T cells produce the third chain of the receptor and now the complete IL-2 receptor is able to bind IL-2 strongly. Note: Naive T cells express the low-affinity IL-2 receptor (IL-2R) complex, made up of the β and γ(c) chains (γc) chain designates the common γ chain (γc). It is called so because it is a common component of several cytokine receptors. Upon activation of T cells by peptide antigen recognition and recognition and co-stimulators (B7), the T cells being activated starts to produce IL-2. At the same time, these T cells express the α chain of the IL-2R ( the third chain that will complete IL-2 receptor), which associates with the β and γc chains to form the high-affinity IL-2 receptor. Binding of IL-2 to its receptor initiates proliferation of the T cells being activated. Thus, IL-2 produced by antigen-activated T cells preferentially binds to and acts on the same T cells ( autocrine effect) The principal actions of IL-2 are to stimulate survival and proliferation of T cells; for this reason IL-2 is also called T cell growth factor. IL-2 stimulates T cells to enter the cell cycle and begin to divide, resulting in an increase in the number of the antigen-specific T cells. This is called ( CLONAL EXPANSION) The role of interleukin-2 (IL-2) and IL-2 receptors in CD4+T cell proliferation: Naive T cells express the low-affinity IL-2 receptor (IL-2R) complex, made up of the β and γc chains (γc designates the common γ chain—so called because it is a component of the receptors for several cytokines). On activation by antigen recognition and co-stimulation, the cells produce IL-2 and express the α chain of the IL-2R, which associates with the β and γc chains to form the high-affinity IL-2 receptor. Binding of IL-2 to its receptor initiates proliferation of the T cells that recognized the antigen. APC, antigen-presenting cell. CD8+ T lymphocytes that recognize antigen and costimulators do not appear to secrete large amounts of IL-2 Activated CD8 T cells proliferate prodigiously during immune responses. Antigen recognition and co-stimulation are able to drive the proliferation of CD8+ T cells without a requirement for much IL-2. However, in some cases, CD8+ T lymphocytes activation requires help from CD4+ helper cells to achieve full activation CLONAL EXPANSION Within 1 or 2 days after activation, T lymphocytes begin to proliferate, resulting in expansion of the antigen-specific clone that was activated in response to recognition of the microbial ( or foreign) peptide antigen on MCH and co-stimulatory molecules (B7). This expansion helps the adaptive immune response to produce a large pool of antigenspecific lymphocytes from which effector cells can be generated to combat (fight) infection Clonal Expasion of Activated CD8 + T cells: The magnitude of CD8+ T cells clonal expansion is remarkable. At the peak of some viral infections, which may be within a week after the infection, as many as 10% to 20% of all of the CD+ T cells population in the body are the ones that are effector cells to combat the virus that causes infection and initiated the immune response. It is estimated that clonal expansion of a particular clone of CD8+ T cells may involve more than 100,000-fold increase in the number of CD8+ T cells specific for the virus that triggered the immune response Clonal Expansion of Activated CD4+ T cells((appears to be much less than that of CD8+ cells)) The magnitude of clonal expansion of CD8+ T cells and CD4+ T cells may reflect differences in their functions. CTLs are effector cells that themselves kill infected cells, so that many CTLs may be needed to kill large numbers of infected cells. By contrast, each CD4+ effector cell secretes cytokines that activate many other effector cells such as macrophages , B cells, and even CD8 T cells. So a relatively smaller number of cytokine producers helper T cells may be needed to combat infection Special Features of Clonal Expansion: First, this enormous expansion of T cells specific for a microbe is not accompanied by a detectable increase in “bystander” cells that do not recognize that microbe. Second, even in infections with complex microbes that contain many protein antigens, a majority of the expanded clones are specific for only a few, and often less than five immunodominant peptides of that microbe. . Differentiation of Naïve T Cells Into Effector Cells Differentiated effector CD4+ or CD8+ T cells start to appear within 3 or 4 days after exposure to microbes. The differentiation process involves of changes in gene expression (e.g., the activation of genes encoding cytokines in CD4 + and CD8+ T cells or cytotoxic proteins production in CD8+ T cells ( granzyme and perforin). After differentiating into effector cells, these cells leave the peripheral lymphoid organs and migrate to the blood stream and then to infection site ( some helper T cells migrate to the margin of B cell zone to help activating B cells) At infection sites , effector T cells ( CD4+/helper and CD8/cytotoxic) again encounter the microbial antigens presented on MHC molecules ((on MHC-II on macrophages and B cells, and MHC-I on infected cells ) and get ACTIVATED ( this activation is different from activation of naïve T cells). In this case, upon recognition of microbial peptide antigens , effector T cells respond in ways that serve to eradicate infected cells ( cytotoxic T cells) or activation of macrophages ( helper T cells) to kill or arrest replication of intracellular microbes that replicate within macrophages ( in phagosome), or helping in B cell activation CD4+ Effector T cells (helper T cells) Helping of other cells by helper T cells is mediated by 1- Surface molecules ( CD40L) 2- Cytokines These molecules are important in the activation of phagocytes and B lymphocytes ( the cells the CD4 helper cells help) 1- Role of Surface molecules ( CD40L) of helper cells in the activation of phagocytes and B lymphocytes (the cells the CD4 helper cells help) The most important cell surface protein involved in the effector function of helper T cells is CD40 ligand (CD40L). The CD40L gene is expressed in activated CD4+ T cells CD40L binds to its receptor, CD40, which is expressed mainly on macrophages, B Lymphocytes ((and dendritic cells)) Engagement of CD40 L (on effector helper T cells) with CD40 ( on macrophages and B cells) activates these cells Note: Remember that interaction of CD40L expressed on T cells at the beginning of the activation process of NAÏVE T cells. In this case, binding of CD40L on T cells to CD40 on dendritic cells results in increase expression of co-stimulators on DCs ( B7) (feed back loop to amplify the second signal) In addition, binding of CD40 L on T cells to CD40 on DC, stimulate the production of certain cytokines by DCs that affect the activation and Differention of T cells (mainly + T cells) The molecules involved in the effector functions of CD4+ helper T cells. CD4+ T cells that have differentiated into effector cells express CD40L and secrete cytokines. CD40L binds to CD40 on macrophages or B lymphocytes, and cytokines bind to their receptors on the same cells ( macrophages and B cells) The combination of signals delivered by CD40 and cytokine receptors activates macrophages in cell-mediated immunity (A) and activates B cells to produce antibodies in humoral immune responses (B). 2- Role of Cytokine produced by effector helper T cells in the activation of phagocytes and B lymphocytes ( the cells the CD4 helper cells help) It has been known for many years that the immune system responds very differently to different microbes. For instance, intracellular microbes such as Mycobacterium tuberculosis are ingested by phagocytes but resist intracellular killing. The adaptive immune response to such microbes results in the activation of the phagocytes to kill the ingested microbes (provided that the microbe is within a phagosomal compartment and not in the cytosol). In striking contrast, helminthic parasites are too large to be phagocytosed, and the immune response to helminths is dominated by the production of immunoglobulin E (IgE) antibodies and the activation of Eosinophils . IgE antibody binds to the helminths, and Eosinophils destroy the helminths by recognition of the Fc region of IgE antibodies bound to the parasite ( ADCC). Both types of immune responses are dependent on CD4+ helper T cells, but for many years it was not clear how the CD4+helper cells are able to stimulate such distinct immune effector mechanisms. This puzzle was answered by the discovery of functionally distinct subpopulations of CD4+ effector T cells that are distinguished by the cytokines they produce, Th1 and Th2 helper T cells CD4+ helper T cells may differentiate into several subsets of effector cells that produce distinct sets of cytokines that perform different functions There are 4 subsets of helper T cells, these are 1) 2) 3) 4) TH1 cells ( helper 1) TH2 cells ( helper 2) TH17 cells because its signature cytokine is IL-17. Regulatory T cells play role in immunologic peripheral tolerance [unresponsiveness]. TH1 and TH2 cells may be distinguished based on: 1. The cytokines they produce 2. The cytokine receptors they express 3. Adhesion molecules they express Note: Comparable data are not yet available for the TH17 subset. It also is likely that many activated CD4+ T cells produce various mixtures of cytokines and therefore cannot be readily classified into these subsets. TH1 cells cytokines: These cytokines activate macrophages to increase their phagocytic activity as well as to increase their killing activity of microbes inside them . These are key component of cell-mediated immunity The most important cytokine produced by TH1 cells is interferon-γ(IFN-γ), 1- IFN-γ is a potent activator of macrophages that will increase their killing activities ( this will kill microbes inside these macrophages or at least restrict its replication) 2- IFN-γ also stimulates the production of antibody isotypes such as IgG ( class switching IgM to IgG) that have the following functions: A- promote the phagocytosis of microbes ( promote opsonization such as IgG) ((because these antibodies bind directly to phagocyte Fc receptors)) B- Activate complement, generating products that bind to microbial surface. phagocyte complement receptors. Bind to these complement products by complement receptors ( promote opsonization) 3- IFN-γ also stimulates the expression of class II MHC molecules and B7 costimulators on macrophages and dendritic cells, and this action of IFN-γ may serve to amplify T cell responses. 4- TH1 cells may also produce TNF-alpha TH2 cytokines: FUNCTIONS 1- Stimulate Eosinophil-mediated immunity, which is especially effective against helminthic parasites 1- IL-4, which stimulates the production of IgE antibodies ( class switching) 2- IL-5, which activates Eosinophils to increase the expression of Fc-epsilon-R2. IgE antibodies bind to parasites . Eosinophils have Fc receptor of IgE antibody ( ADCC) ….killing of the parasite 2- Barrier immunity: IL-4 and IL-13, promote the expulsion of parasites from mucosal organs and inhibit the entry of microbes by stimulating mucus secretion. This type of host defense sometimes is called “barrier immunity” because it blocks the entry of microbes at mucosal barriers. IgE activates mast cells ( Type I hypersensitivity-discussed later) 3- Tissue repair: Th2-mediated macrophage activation that enhances certain functions of macrophages such as synthesis of substances involved in tissue repair such as extracellular matrix proteins as well as activation of fibroblast which also produce substances of extracellular matrix . 4- Inhibition of the microbicidal activities of macrophages: Some Th2 cytokines , such as IL-4, IL-10, and IL-13, inhibit the microbicidal activities of macrophages and thus suppress Th1 cell–mediated immunity. (IL-4, IL-10, and IL-13 cytokines interfere with the effect of TH1 cytokines that increase the killing activity of macrophages ) Therefore, the efficacy of cell-mediated immune responses against a microbe may be determined by a balance between the activation of Th1 and Th2 cells in response to that microbe. TH17 Function: TH17 cells secrete the cytokines IL-17 and IL-22 and are the principal mediators of inflammation in a number of immunologic reactions against bacterial and fungal infections and maintaining epithelial barrier functions (production of anti-microbial peptides) IL-17 and IL-22 : (Based on animal models), these cytokines have been shown to be involved in multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis, and is increasingly being implicated in these diseases in humans. The functions of TH1 cells. TH1 cells produce the cytokine interferon-γ (IFN-γ), which activates phagocytes to kill ingested microbes and stimulates the production of antibodies that promote the ingestion of microbes by the phagocytes. The functions of TH2 cells. TH2 cells produce the cytokines IL-4, which stimulates the production of immunoglobulin E (IgE) antibody. IL-5, which activates eosinophils. IgE participates in the activation of mast cells by protein antigens and coats helminthes, and eosinophils destroy the helminthes. . The functions of TH17 cells. TH17 cells produce the cytokines IL-17, which induces production of chemokines and other cytokines from various cells. Recruitment of neutrophils (and monocytes, not shown) into the site of inflammation. Some of the cytokines made by TH17 cells, notably IL-22, function to maintain epithelial barrier function in the intestinal tract and other tissues such as production of antimicrobial peptides. During the activation process of CD4 T cells…… the development of TH1, TH2, and TH17 subsets is NOT a random process but is regulated by the stimuli that naive CD4+ T cells receive during the activation process when they encounter microbial antigens I- The Development of TH1 cells : In response to many bacteria and viruses , dendritic cells and macrophages produce a cytokine called IL-12, and NK cells produce IFN-γ. During the activation of naive CD4 T cells , exposure to such cytokines promote the differentiation of the T cells to the TH1 subset. Accordingly, the innate immune response—in this case, IL-12 production by DCs and IFN-γ production by NK cells—influences the nature of the subsequent adaptive immune response, driving it toward TH1 cells. II- The development of TH2 cells is stimulated by the cytokine IL-4 The main source of IL-4 is TH2 cells. It appears that if an infectious microbe does not induce IL-12 production by DCs, as may be the case with helminths, the T cells themselves are programmed produce IL-4 spontaneously ( in other words, in the absence of IL-12, CD4 T cells automatically, produce IL-4 during the activation process that derive their differentiation into TH2) Another source for IL-4: Helminths may activate cells of the mast cell lineage to secrete IL-4, which also promote differentiation of CD4 T cells to the TH2 subset. III The development and maintenance of TH17 cells The differentiation of CD4 T cells into TH17 cells require the exposure of these cells to certain inflammatory cytokines during the activation process such as IL-6 and IL-1 (produced by macrophages and dendritic cells) IL-23 (which is related to IL-12 and made by the same cells) Transforming Growth Facto-beta TGF-β (particularly in mice). Defining the stimuli for development of this T cell subset is an area of active investigation The differentiation of CD4+ helper T cells into TH1, TH2, and TH17 subsets is an excellent example of the specialization of adaptive immunity, illustrating how immune responses to different types of microbes are designed to be most effective against these microbes. Important Notes: Once one of these populations helper T cells develops, it produces cytokines that enhance the differentiation of T cells toward that subset and inhibits development of the other populations. This “cross-regulation” may lead to increasing polarization of the response toward one population. There is emerging evidence that some differentiated CD4+ T cells can convert from one subset into another, under certain conditions CD8+ T lymphocytes activated by antigen and co-stimulators differentiate into Cytolytic T Cells (CTLs )/ also called Cytotixic T cells Effector CD8+ T cell (CTLs) kill infected cells that display microbial peptides on MHC-I by : A- Secreting Proteins that create pores in the membranes of the infected cells perforin and Granzyme that induce apoptosis ( by activating caspases) in infected cells B- In addition Effector CD+T cells express Fas ligand ( death ligand) . Binding of Fas L ( death ligand) on Effector CD8+ T cell to Fas Receptor (Death receptor) on infected cells activate caspases in infected cells that lead to apoptosis The evidence of differentiation of naive CD8+ T cells into effector CTLs is the production of the molecules/proteins ( mentioned above) that are needed to kill infected cells. DEVELOPMENT OF MEMORY T LYMPHOCYTES: A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells. However, they require signals delivered by certain cytokines, including IL-7, in order to stay alive. Factors involved in determining whether the progeny of antigen-stimulated lymphocytes will differentiate into effector cells or memory cells are not known Memory T cells can be found in lymphoid organs, in mucosal tissues, and in the circulation. Memory T cells do not continue to produce cytokines or kill infected cells , but they may do so rapidly on encountering the antigen that they recognize after undergoing rabid clonal expansion. DECLINE OF THE IMMUNE RESPONSE: During an immune response , a very high number of antigen-specific effector T lymphocytes are generated to combat infection Once the microbe is eradicated, the system has to return to its steady state, called homeostasis ( this implies that most of the generated effector T cells need to be eliminated- MISSION ACOMBLISHED) , so that the immune system is prepared to respond to the next infectious pathogen. During an immune response against a particular microbe, activation, proliferation , differentiation of naïve T cells as well as survival of effector T cells are maintained by: 1. Continuous detection of the microbial antigen 2. Co-stimulatory signals from CD28 ( by binding to be B7 on Macrophages and B cells), 3. Cytokines such as IL-2. Once an infection is cleared and the stimuli for naïve T lymphocyte activation and survival if effector cells disappear As a result, these effector cells start to cells die by a process of apoptosis (programmed cell death). The immune response starts to subside/ decline within 1 or 2 weeks after the infection has been eradicated. The only sign/evidence about the occurrence of a T cell–mediated immune response against a particular microbe is the detection of a pool of surviving memory T lymphocytes specific to that microbe.