Download BIOT 307: MOLECULAR IMMUNOLOGY

BIOT 307: MOLECULAR
IMMUNOLOGY
Cells and Organs
March 7-9, 2011
IMMUNE CELLS
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B lymphocytes
T “
NK
Macrophages
Dendritic Cells
Antigen Specific
Antigen-presenting cells
(APCs), non-specific
characteristic (See Fig. 2-2)
• antigen receptors - B, T, NK
• cell surface markers – all
• functions - all
NOT SHOWN
IN CLASS
TYPES OF IMMUNE CELLS
LYMPH SYSTEM
• Multiple functions
• Branched
• All tissues of body
• Lymph vessels & nodes
• MALT = digestive,
respiratory, genitourinary
lymphoid tissue, Peyer’s
Patches, tonsils, appendix
• Bone marrow – all long
bones
• Thymus
• Spleen
SPLEEN: Secondary Lymphoid Organ
B Cells
GALT
LYMPH NODES
HEMATOPOESIS
DEVELOPMENT OF IMMUNE CELLS
Bone Marrow
IL1-7, CSF – G, GM, M
C-kit ligand
<----- differentiation
Non-self
renewing
Thymus
Granulocytes
Look alike
DNA
rearrangements
TH , TC subsets
B cell subsets
Myeloid/Erythroid
progenitor
Red cell
Stromal cells = green cords
Bone and Marrow
CELL SURFACE MARKERS
SOME HEMOPOETIC CYTOKINES
FATE AND DEVELOPMENT OF B CELLS
B-CELL DEVELOPMENT
Naive
Structural and functional changes
Also T-independent
activation
Spleen
B CELLS
• Move from BM to spleen
– Marginal zone
– Mature follicular circulating B cells
• Ag stimulation  Terminal division into plasma
cells  Abs
• Transitional B cells
– Naive, non-circulating located in spleen's marginal
zone
– Long-lived follicular B cells = conventional or B2, IgM+,
IgD+
B CELLS
• Function = antibody production
• Activated by Ag
– TC-dependent and TC-independent
• Produce Ig (IgG, IgA, IgM, IgD, IgE) of unique Ag
specificity
• Ag recognized is in native/natural, i.e.,
undigested state
– Protein, Polysaccharide, Glycolipid, Nucleic acids
• B Cell Receptors (BCRs) = membrane-bound Ig
(antibody) Ag specific molecules
SPLEEN: Secondary Lymphoid Organ
B Cells
B CELLS
• B cell subsets
– CD5- = marginal zone B cells
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Spleen
Resting mature B cells
Limited repertoire
Recognize common bacterial Ag
– CD5- = B2 B cells conventional (follicular)
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Major B cell
B2 B expresses IgM and IgD
95% recirculating B cells
From secondary lymphoid organs
Long-lived
TC dependent B cell responses to most protein Ag
B CELLS
• B cell subsets
– CD5+ = B1 B cells
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5% of B cell
expresses IgM
Pleural and peritoneal cavities
Self-renewal outside bone marrow
Limited ability to rearrange  limited diversity/repertoire
Recognize common bacterial Ags, e.g., carbohydrate and
lipid
• Recognition skewed toward TC-independent Ag
• Not  memory B cells
B CELL SUBSET COMPARISON
Janeway
B CELL: MAJOR SURFACE MOLECULES
• Immunoglobulins
– Clonal selection by Ag
– 1 antigen determinant per B cell
– = major B-cell receptor (BCR) molecule
– Antigen types recognized
• protein, polysaccharide, glycolipid, and nucleic acids
• Undigested or natural state
B CELL: MAJOR SURFACE MOLECULES
• Fc receptors
– Fc = constant region of Ig
– Modulates events after Ag binds to BCR
• Complement receptors
– CR1 (CD-35) and CD2 (CD21) bind certain
complement products
– Enable binding of Ag-Ab-complement complexes
• Maturation receptor (CD40)
– Binds to CD40 ligand on T cells
– Enhances survival and maturation into plasma cells
B CELL: MAJOR SURFACE MOLECULES
• T cell-derived factor receptors
– CD80 (BC-7), CD-86 (BC-2) on B cells interact with
CD28 and CTLA-40 on T cells. CD28 and CTLA-40 are
regulatory molecules.
– On activated B cells
– Bind to corresponding molecules on T cells (TCdependent)
• MHC proteins (Class I and II)
– Ag presentation to T cells
– Class II turns B cells into APCs
T CELLS
• Only recognize protein antigen in the form of
peptides bound to MHC molecules
– MHC restriction
• Protein antigen found on APCs
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B cells, macrophages and dendritic cells
Virus-infected cells
Graft cells
Cancer cells
• Activated when T cell receptors (TCRs) on T cells
recognize
T CELL FUNCTIONS
1. Regulatory, i.e., modulate activities of
– Other T cells
– Dendritic cells (DCs)
– Macrophages
– B cells
T CELL FUNCTIONS
2. Mediate CMI through production of
cytokines and chemokines
Promote proliferation/differentiation of T cells
Attract/activate other elements of immune
system:
• inflammation, delayed type hypersensitivity (DTH),
resistance to infection by intracellular pathogens
T CELL FUNCTIONS
3. Interact with and destroy target cells
– Virus-infected cells
– Foreign tissues
– Tumor cells
CELLS IN THYMUS
• Maturation
– Thymic stromal cells release hormones and
cytokines and express ligands
• CD4 and CD8 αβ T cells  CD4+ and CD8+
• γδ TC 
– T reg
– NK
– Intraepithelial lymphocytes
• Thymic stromal cells and APCs (macrophages
and DCs)  MHC recognition of MHC I/II
molecules
MATURATION
MORE NOTES FOR PREVIOUS PAGE: Memory T cell, confer
long-term immunity.
Tregs CD4+CD25+, some of which are generated from the
thymus, are thought to suppress CD4+ and CD8+ T cells
B-cell development in the bone marrow:
common lymphocyte precursors (CLP)  immature B
lineage-committed cells (pro-B)  Ig heavy chain gene
rearrangements in pre-B cell stage -->naïve mature B cells
leave bone marrow w/ the IgM receptor  secondary
lymphoid tissues, where they encounter antigens and are
activated; secrete IgM and may isotype switch to IgG. Some
differentiate into plasma cells, secreting antigen-specific IgG
antibodies essential for long-term immune response.
NOTES FOR PREVIOUS PAGE: Schematic representation of T cell development. T cells
originate from the common lymphoid progenitor cells in the bone marrow. They
migrate as immature precursor T cells via the bloodstream into the thymus, which they
populate as thymocytes. The thymocytes go through a series of maturation steps
including distinct changes in the expression of cell surface receptors, such as the CD3
signaling complex (not shown) and the coreceptors CD4 and CD8, and the
rearrangement of their antigen receptor (T cell receptor, TCR) genes. More than 98% of
the thymocytes die during maturation by apoptosis (†), as they undergo positive
selection for their TCR's compatibility with self-major histocompatibility molecules, and
negative selection against those T cells that express TCRs reactive to autoantigenic
peptides. In humans, the vast majority of peripheral blood T cells expresses TCRs
consisting of α and β chains (αβ T cells). A small group of peripheral T cells bears an
alternative TCR composed of γ and δ chains (γ/δ T cells). αβ and γδ T cells diverge early
in T cell development. Whereas αβ T cells are responsible for the classical helper or
cytotoxic T cell responses, the function of the γδ T cells within the immune system is
largely unknown. αβ T cells that survive thymic selection lose expression of either CD4 or
CD8, increase the level of expression of the TCR, and leave the thymus to form the
peripheral T cell repertoire.Skapenko et al. Arthritis Research & Therapy 2005 7(Suppl
2):S4 doi:10.1186/ar1703
Key T-cell Molecules and Functions
T cell Ag receptor
TCR
Defines TC
CD4, CD8
TH, TC
Divides TC into 2 types
CD40 ligand
CD154
Interacts with CD40 on B
cells  BC activation
Co-stimulatory molecules
TNFR superfamily
CD28 family
adhesion molecs.
IL-1 receptor
Helps activate TC
MHC Class I, II
CD45
Signal transduction
THELPER ACTIVATION
• MHC II peptide (antigen) complex on APC
binds CD4+ and TCR 
proliferation, differentiation 
Ag-specific effector cell clones
• Type of Ag and APC  activate unique
cytokine profiles  3 functional TH types
– TH1 secrete IFN-γ, IL-2, TNF-β (CMI)
– TH2 secrete IL-4, 5, 10, 13 (HI)
– TH17 secrete IL-17 (inflammation)
CD4+, THELPER
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Stimulates B cell antibody production
Activates macrophages and TC
Maintain memory
Main responder to antigens presented by MHC II
– CD4 binds directly to region of APC’s MHC II molecule
• Four types based on cytokine secretion and
functional activities: TH1, TH2, TH17 and Treg
• 50-75% T cells
CD8+, CYTOXIC (TC)
• Kill virus-infected cells, transplanted tissue,
cancer cells
• Two mechanisms:
– Bind to cell surface and inject perforin and
granzymes
– Bind to Fas ligands  apoptosis
CD8+, CYTOXIC (TC)
• Naive TC activation involves
– co-stimulation by DCs/cytokines
– Proliferate when TCR recognizes foreign processed
(peptide) Ag associated with MHC I (crosspresentation)
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Effector cells secrete IFN-γ
Subsets according to cytokines secreted
Class 1 MHC restricted
20-40% T cells
TREG
• Suppressor TC
• CD4+, CD25+ (IL-2 receptor α chain), FOX P3+
expressing FOXP3 – transcription factor
• = 5-10% T cells
• Prevent autoimmune disease
• Diminish effector responses to cancer and
infections
γδ+ TC
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CD4-, CD8-, CD3+
Function in innate manner
Generate memory
Less TCR diversity but TCR genes rearrange
Recognize phosphorylated microbial molecules
and lipid antigens not presented by MHC –
soluble molecules
• Gut mucosa
• IFN-γ, THF-α
Continued