T/b Cell Mediated Immunity

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Positive TCR Selection

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Found in cortex thymus. Double negative thymocytes (CD3-,CD4-,CD8-). Progenitor cells develop into positive selection. Self MHCI and self MHCII binding with moderate affinity gets survival. Differentiate into CD8 or CD4

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Negative TCR Selection

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Found in cortico-medullary thymus. T cells dialogue with dendritic cells. High affinity self peptides and MHCI/MHCII destroyed. Remove self reactive T cells.

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Location of TCR development

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Thymus

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Thymus Cortex

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Epithelial cells create thymic stroma composed of macrophages and thymocytes

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Thymus Medulla

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Epithelial cells. Dendritic cells self reactive screening. Macrophages remove dead lymphocytes and Hassall's corpuscle site of cell destruction.

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TCR structure and location

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Heterodimer of alpha and beta chain variable region. Membrane bound. CD3 [epsilon,delta][gamma,epsilon][zeta,zeta]

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CD4 structure

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T cell co-receptor. Four domains D1,D2,D3,D4. Found on helper T cell. Contact MHCII at beta2

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CD8

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T cell co-receptor. Alpha and beta domain. Found on cytotoxic T cell. Contact MHCI at alpha3.

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Variable domain TCR response

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Multiple gene segment, somatic recombination, junctional diversity (P/N nucleotide division), RSS recombination. No class switching or hypermutaiton.

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Variable domain TCR

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Alpha chain on chromosome 14 (V+J)

Beta chain on chromosome 7 (V+D)

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AIRE

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autoimmune regulator is a transcription factor turns on peripheral genes in thymus

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Naive T cell stimulation

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TCR signal and B7 co-stimulation from APC. Lack of stimulation lead to anergy

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Naive T cell loaction

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Recirculating of T cell in SLT. Enter lymphatic drainage via HEV, requires homing.

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Homing naive T cell

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Cell adhesion molecules and chemokines CCL19+CCL21 produced by stromal and dendritic cells. Glycan and selectin slows movement

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Naive T cell adhesion

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L selectin binds to GlyCAM slows lymphocyte rolling. Activated LFA binds to ICAM. Anchor T cell leads to diapedesis

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Naive T cell adhesion molecules

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link dendritic cell to t cell. ICAM-LFA, ICAM3-DC-Sign

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B7(CD80)

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secondary signal for activation by APC. Ligates with T cell CD28. Stimulates T cell differentiation and proliferation

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CTLA-4

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Cytotoxic T lymphoctye Associated Antigen. Present on activated T cell that has high affinity for B7. Delivers inhibitory signal limits cell proliferation

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Anti-CTLV4/Ipilimumab

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Monoclonal antibody against CTLA4 blocks B7-CTLA4 ligation. T cell remain active enhance immune system

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Dendritic cell

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APC originating in bone marrow myeloid stem cell. Located in all peripheral tissues. Phagocytize antigen and migrate to lymph node.

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Mature dendritic cell characterisitcs

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Stop phagocytosis, develop finger like extensions to increase surface area. Expression of MHC with co receptors

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Dendritic cell co-receptors and ligands

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Receptors (ligand): B7(CD28 Tcell), CCR7(CCL21 SLT), DC-SIGN(ICAM3 Tcell). ICAM1/2(LFA T cell)

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IL-2 function

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Stimulate T cell proliferation and differentiation to effector. Produced by activated T cell. Autocrine signalling.

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IL-2 receptor naive vs active t cell

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Naive t cell has gamma and beta chain for low affinity IL-2 and active has gamma, beta, and alpha chain for high affinity.

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Transcription Factor TH1

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T-bet

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Cytokine Exposure TH1

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IL-12 from DC/macrophages and INF-gamma from NK cells

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Cytokine Profile TH1

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INF-gamma (positive feedback but inhibits TH2 and TH17) and CD40L.

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Immune Role of TH1

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Activate macrophages and kill resident bacteria. Cell mediated IR

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Cytokine Exposure TH2

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IL-4 from eosinophils, basophils, mast, or NK

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Transcription Factor TH2

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GATA 3

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Cytokine Profile TH2

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IL-4 (positive feedback but inhibits TH17), IL-5, IL-13, CD40L, IL-10 and TGF-beta (both inhibit TH1 and macrophages)

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Immune Role TH2

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IgE production, recruit eosiniphils, mast cells, basophils, protect mucosa parasites. Humoral immunity bias due to Ab dominated

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Cytokine Exposure TH17

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IL-6, IL-23, TGF-beta (all from DC)

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Transcription Factor TH17

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ROR-gammaT

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Cytokine Profile TH17

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IL-17

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Immune Role TH17

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IL-17 triggers tissue to produce:

IL-6 (Inflammation), CXCL8,12 (recruit neutrophil), G-CSF and GM-CSF (stimulate neutrophil release from bone marrow). Protects against extracellular bacteria and fungi.

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Cytokine Exposure TFH

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IL-6

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Transcription Factor TFH

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Bcl-6

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TFH's CXCR and ICOS

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CXCR ligates with CXCL13 produced by stromal cells in B cell follicle. Causes migration from T cell area to B cell area. ICOS binds to ICOSL of DC

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Cytokine Profile TFH

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IFN-gamma induces IgG1/IgG3, IL-4 induces IgE, and CD40L to signal CD40 on B cell

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Immune Role TFH

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Stimulate B cell for:

somatic hypermutation, affinity maturation, class switching. Bias towards humoral immunity Ab dominated

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Origin Natural Treg

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immature thymocyte within thymus. High TCR affinity for self peptide but not enough to be deleted. 10-15% CD4 cells

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Transcription Factor Natural Treg

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FoxP3

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Receptors on Natural Treg

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CD4, CD25, CD62L (L-selectin), CTLA4 (monopolizes APC B7 to lead to T cell anergy).

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Cytokine Profile Natural Treg

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IL-10 and TGF-beta inhibit T cell proliferation

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Immune Role Natural Treg

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Prevent autoimmune response and curtail normal protective immune response

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Origin Induced Treg

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Naive CD4 T cell in periphery in absence of infection. DC produce lots of TGF-beta. Some IL-6, IL-12, and IFN-gamma

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Transcription Factor Induced Treg

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FoxP3

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Receptors on Induced Treg

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CD25 and CD4

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Cytokine Profile Induced Treg

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IL-10 and TGF-beta inhibit cell proliferation. TGF-beta positive feedback.

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Immune Role Induced Treg

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suppress immune response, inflammation

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Why regulate macrophages

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Prevent local tissue damage, toxic microbiological agent releaced

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Cytokines that inhibit macrophages

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TGF-beta and IL-10. Treg and TH2 produces them

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Granuloma

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inflamed nodules made of macrophages. Form around non-degradable foreign bodies or around chronic intracellular infection. Central core giant macrophages. Outer ring is TH

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Naive B cell activation

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cross-linking of BCR to multiple antigen epitopes and co-receptors

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Thymus dependent antigens

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Require TFH and TH2 to activate B cell. Cognate interaction significant

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Cognate interaction of T/B cell

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B cell recognizes surface epitope and T cell recognizes intracellular protein

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Thymus independent antigen

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Activate naive B cell without T cell influence. High density of repetitive epitopes like polysaccharides. (capsule) Produces mostly IgM without class switching. Fetus to age 5. Found in peritoneum and pleural cavity

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Mitogens

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substance that cause differentiation of B cell regardless of specificity. Polyclonal activation. High dose of LPS via TLR-4

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T cell synapse

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Contact point between T cell and DC

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Transcription factors activated during T-DC synapse

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NFAT:nuclear factor of activated T cell

NFKB:nuclear factor kappa B

AP-1:Fos/Jun protein

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Protein tyrosine kinase

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enzyme that phosphorylates tyrosine. FYN associated with CD3, Lck associated with CD4 and CD8, ZAP70 cytoplasmic protein

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ITAM

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immunoreceptor tyrosine based activation motif. Present in cytoplasmic tail of CD3 (gamma, delta, epsilon, zeta) binds ZAP70