Surface Immunoglobulin or B-Cell receptor

Antibody

T-Cell Receptor

• The heavy chains of surface immunoglobulin also known as the B-cell receptor, and antibody (blue), light chain (red)
• The alpha chain of the TCR
• The beta chain of the TCR

• Whereas TCRs only recognize short degraded fragments of a pathogen, proteins bound by MHC, the immunoglovulin receptors, and soluble antibodies of B cells directly recognize the native conformations of peptides as well as many other types of macromolecules present on pathogen surfaces
• Carbs
• Proteoglycans
• Glycoproteins
• Glycolipids

• After recovering from infection w/ measels virus, a persons body fluids contain many different antibodies that can bind to the measels virus and prevent reinfection
• None bind to unrelated virus (ie influenza)

• The CD8 co-receptor binds to Alpha3 domain of MHC I heavy chain, ensuring that MHC I molecules present peptides only to CD8 T cells
• In complementary fashion the CD4 co-receptor binds to Beta2 domain of MHC II ensuring that peptides bound by MHC II stimulate only CD4 T cells

• Receptor of CD8 T cell specific for one peptide only w/ MHC I molecule (co-recognition) called MHC restriction
• Does not recognize some peptide when bound to a different MHC I molecule
• No recognition complex bound with different peptide

• Each lymphocyte has only receptors of a single specificity
• When a particular B or T Cell is activated and proliferates, all progeny are clones and identical to the initial activated cell

• Positive Selection: by MHC: peptide complexes on thymic cells ensures that the T cells that survive are able to interact w/ self MHC molecules
• Negative Selection: macrophages in thymic medulla ensures that T cells that react strongly against self-ag presented by MHC are eliminated: Resulting native T cell repertoire represent small % of total diversity of T cell are generated

1. T cell precursor - rearranges TCR genes in 
2. thymus(+/-) selection: thymus
3. Mature T cells migrate to peripheral lymphoid organs - are activated
4. Proliferation - Infection elimination

1. Alpha/Beta

• Classical T cells (CD4, CD8, CD3)
• Recognize antigen using MHC

1. Gamma/Delta

• Similar structures
• Encoded by different set of rearranging gene segment gives rise to different functions

• Antigen receptor = 8 polypeptides = TCR complex
• AlphaBeta TCR interacts w/ 1delta/1gamma/2epsilon CD3
• Transport TCR to cell surface
• Transduction of signals to cells interior
• TCR itself does not have much intra-cellular signaling capacity
• CD3 is a multi-subunit, cell surface and intra-cellular signaling molecule
• All T cells are CD3+
• Interfering with CD3 signaling (eg Fab')2 protion of Ab to CD3 is being explored clinically as a method to interfere with autoimmune diseases (Type I diabetes)

CD4/CD8

• CD4: D1-D4
• MHC II
• A1/B1 receptor
• A2/B2 membrane
• D2-B1, D1-B2
• CD8: Alpha and Beta chain
• MHC I
• Alpha 1/Alpha 2 receptor
• Alpha 3 bound to membrane
• Beta2Microglobulin

• Binding of the TCR & its co-receptor CD4 to the peptide MHC II complex on DC delivers a signal
• Induces clonal expasion of T cells only when co-stim (2) is also given by binding CD28-B7
• Both CD28 and B7 are members of the immunoglobulin superfamily
• 2 Forms: B7.1 (CD80), B7.2 (CD86)

• Phagocytosis of bacteria by macro. & their breakdown in the phagolysosomes leads to the release of substances such as LPS, which induce the expansion of co-stim B7 on macro. surface
• Peptides dericed form degredation of bacterial proteins in the macro. vesicular system are bound by MHC II & presented on macro. surface
• Activation of naive T cells is accomplished by comb. of B7-binding to CD28 & peptide:MHC complexes binding TCR

• A naive T cell can be activated by only a APC carrying both a specific peptide:MHC complex & co-stim on surface. this combo results in naive T cells receipt of signal 1 from TCR & signal 2 from co-stim
• When the APC has specific peptide:MHC complex to deliver signal (1) but no co-stim (2), T cell enter non responsive anergic state
• Only signal 2 = no effect observed T cell

• Resting T cell ITAMs are not phosphorylated
• Binding of MHC ligand to T Cell receptor leads to phosphorylation of the ITAMs by receptor associate kinases
• When the co-receptor binds to the MHC ligand, ZAP-70 binds to phosphorylated chain ITAMs and is phosphorylated and activated by Lck

• (CD80/CD86) - B7
• CTLA4 - more tightly bound
• Inhibitory
• CD28 (activating)
• MHC:TCR (activating)

• CTLA4 - more tightly bound than B7 
• PD1
• Instead of ITAMs for intracellular signaling, these have ITIMs: Immunotyrosine INHIBITORY motifs

• IL-2 is crucial for T cell expansion (proliferation) and survival
• Only made by activated T cells
• naive T cells and activated T cells have IL-2 receptors on cell surface. The exact composition of the IL-2R varies between naive + activated T cells
• Low affinity (beta/gamma) High affinity (alpha/beta/gamma)

1. Naive CD8 T cell activated directly by a virus infected cell (DC-high B7) - makes IL-2 driving proliferation
2. APC stimulates effector CD4 Tcell, which in turn activates APC - activated APC expresses B7, which co-stims naive CD8 T cell
3. APC activates CD4 T cell to make IL-2 and naive CD8 T cell to express IL-2 receptors - IL-2 secreted by acivated CD4 T cell is bound by CD8 T cell

• Resting naive T cells - express L-selectin, home to lymph nodes & relatively low levels of the other adhesion molecules CD2/LFA-1 - upon activation L-selectin ceases & LFA-1 increases
• VLA-4 is homing receptor for vascular endothelium at inflammation sites
• Activated T cells: have more CD2 on surfaces, increases adhesion to target cells & higher density of CD44 adhesion
• Alternative splicing of RNA by CD45 causes T cells to express CD45RO isoform which associated with TCR & CD4 makes T cell more sensitive to simulation by lower conc. of peptide:MHC

1. Naive T cells encounter cognate antigen on APCs - are induced to proliferate/differentiate into effector T cells
2. Effector cells recognize cells bearing specific Ags - Naive CD8 --> CD8 cytotoxic effector cells (CTL), kills target cells with peptide bound to MHC I

• CD4 - Th1 or Th2 - MHC II
• Th1 (macro. activation - elimination)
• Th2 (naive T cells - adaptive response)