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T细胞生物学 T Cell Biology Innate and adaptive immunity 3 types of cell,3 types of molecule T Cell Behaviors Maturation Recognition Activation proliferation Differentiation Apoptosis Memory Effector function migration maturation Stages of lymphocyte maturation maturation Pluripotent stem cells give rise to distinct B and T lineages Pluripotent stem cells give rise to distinct B and T lineages. Hematopoietic stem cells (HSCs) give rise to distinct progenitors for various types of blood cells. One of these progenitor populations (shown here) is called a common lymphoid progenitor (CLP). CLPs give rise mainly to B and T cells but may also contribute to NK cells and some dendritic cells (not depicted here). Pro-B cells can eventually differentiate into follicular (FO) B cells, marginal zone (MZ) B cells, and B-1 cells. Pro-T cells may commit to either the αβ or γδ T cell lineages. Commitment to different lineages is driven by various transcription factors, indicated in italics. ILC, innate lymphoid cells. maturation Maturation of T cells in the thymus Maturation of T cells in the thymus. Precursors of T cells travel from the bone marrow through the blood to the thymus. In the thymic cortex, progenitors of αβ T cells express TCRs and CD4 and CD8 coreceptors. Selection processes eliminate selfreactive T cells in the cortex at the double-positive (DP) stage and also single-positive (SP) medullary thymocytes. They promote survival of thymocytes whose TCRs bind self MHC molecules with low affinity. Functional and phenotypic differentiation into CD4+CD8− or CD8+CD4− T cells occurs in the medulla, and mature T cells are released into the circulation. Some double-positive cells differentiate into regulatory T cells (see Chapter 15). The development of γδ T cells is not shown. maturation Structure of the T cell receptor Structure of the T cell receptor. The schematic diagram of the αβ TCR (left) shows the domains of a typical TCR specific for a peptide-MHC complex. The antigen-binding portion of the TCR is formed by the Vβ and Vα domains. The ribbon diagram (right) shows the structure of the extracellular portion of a TCR as revealed by x-ray crystallography. The hypervariable segment loops that form the peptide-MHC binding site are at the top. maturation TCR α and β chain gene recombination and expression TCR α and β chain gene recombination and expression. The sequence of recombination and gene expression events is shown for the TCR β chain (A) and the TCR α chain (B). In the example shown in A, the variable (V) region of the rearranged TCR β chain includes the Vβ1 and Dβ1 gene segments and the third J segment in the Jβ1 cluster. The constant (C) region in this example is encoded by the exons of the Cβ1 gene, depicted for convenience as a single exon. Note that at the TCR β chain locus, rearrangement begins with D-to-J joining followed by V-to-DJ joining. In humans, 14 Jβ segments have been identified, and not all are shown in the figure. In the example shown in B, the V region of the TCR α chain includes the Vα1 gene and the second J segment in the Jα cluster (this cluster is made up of at least 61 Jα segments in humans; not all are shown here). recognition A model for T cell recognition of a peptide-MHC complex recognition Binding of a TCR to a peptide-MHC complex Binding of a TCR to a peptide-MHC complex. The V domains of a TCR are shown interacting with a human class I MHC molecule, HLA-A2, presenting a viral peptide (in yellow). A is a front view and B is a side view of the x-ray crystal structure of the trimolecular MHC-peptide-TCR complex. recognition Functions of different antigen-presenting cells activation Activation of naive and effector T cells by antigen activation Phases of T cell responses activation Components of the TCR complex Components of the TCR complex. The TCR complex of MHCrestricted T cells consists of the αβ TCR non-covalently linked to the CD3 and ζ proteins. The association of these proteins with one another is mediated by charged residues in their transmembrane regions (not shown). activation Ligand-receptor pairs involved in T cell activation Ligand-receptor pairs involved in T cell activation. A, The major surface molecules of CD4+ T cells involved in the activation of these cells (the receptors) and the molecules on APCs (the ligands) recognized by the receptors are shown. CD8+ T cells use most of the same molecules, except that the TCR recognizes peptide–class I MHC complexes, and the coreceptor is CD8, which recognizes class I MHC. Immunoreceptor tyrosine-based activation motifs (ITAMs) are the regions of signaling proteins that are phosphorylated on tyrosine residues and become docking sites for other signaling molecules. CD3 is composed of three polypeptide chains, named γ, δ, and ε, arranged in two pairs (γε and δε) as shown in Figure 7-8; we show CD3 as three protein chains. activation Ligand-receptor pairs involved in T cell activation B, The important properties of the major accessory molecules of T cells, so called because they participate in responses to antigens but are not the receptors for antigen, are summarized. CTLA-4 (CD152) is a receptor for B7 molecules that delivers inhibitory signals; its role in shutting off T cell responses is described in Chapter 9. APC, antigenpresenting cell; ICAM-1, intercellular adhesion molecule 1; LFA-1, leukocyte functionassociated antigen 1; MHC, major histocompatibility complex; TCR, T cell receptor. activation Functions of costimulators in T cell activation Functions of costimulators in T cell activation. A, The resting APC (typically dendritic cells presenting self antigens) expresses few or no costimulators and fails to activate naive T cells. (Antigen recognition without costimulation may make T cells unresponsive [tolerant]; we will discuss this phenomenon in Chapter 15.) B, Microbes and cytokines produced during innate immune responses activate APCs to express costimulators, such as B7 molecules. The APCs (usually presenting microbial antigens) then become capable of activating naive T cells. Activated APCs also produce cytokines such as IL-12, which stimulate the differentiation of naive T cells into effector cells. activation Changes in surface molecules after T cell activation Changes in surface molecules after T cell activation. A, The approximate kinetics of expression of selected molecules during activation of T cells by antigens and costimulators are shown. The illustrative examples include a transcription factor (c-Fos), a cytokine (IL-2), and surface proteins. These proteins are typically expressed at low levels in naive T cells and are induced by activating signals. CTLA-4 is induced 1 to 2 days after initial activation. The kinetics are estimates and will vary with the nature of the antigen, its dose and persistence, and the type of adjuvant. proliferatio n Regulation of IL-2 receptor expression and proliferation Regulation of IL-2 receptor expression. Resting (naive) T lymphocytes express the IL-2Rβγc complex, which has a moderate affinity for IL-2. Activation of the T cells by antigen, costimulators, and IL-2 itself leads to expression of the IL2Rα chain and increased levels of the high-affinity IL-2Rαβγ complex. clonal expansion Clonal expansion of T cells Clonal expansion of T cells. The numbers of CD4+ and CD8+ T cells specific for microbial antigens and the expansion and decline of the cells during immune responses are illustrated. The numbers are approximations based on studies of model microbial and other antigens in inbred mice. Differentiation Properties of TH1, TH2, and TH17 subsets of CD4+ helper T cells Effector Function Effector Function Effector Function Effector Function Effector Function Effector Function apoptosi s apoptosis Memory Development of memory T cells Development of memory T cells. In response to antigen and costimulation, naive T cells differentiate into effector and memory cells. A, According to the linear model of memory T cell differentiation, most effector cells die and some survivors develop into the memory population. B, According to the branched differentiation model, effector and memory cells are alternative fates of activated T cells. Thank You!