T Lymphocyte Surface Molecules

T Cell Receptor

heterodimer of a and b transmembrane chains

extracellular portion has constant and variable domains; hinge region exists between the transmembrane and constant domains

genetic mechanism for diversity is similar to that described for Ig above to 10¹⁶

CD3 Complex

four polypeptide chains around TCR that transport it to surface

defines a T Cell and is always associated with TCR

along with homodimer of zeta chains is involved in signal transduction via Tyr kinases

zeta is linked to Fyn which Þ IP₃Þ calcineurin Þ proliferation and differentiation

Zap 70 also feeds this path by Ras activation

CD3 is distinct from CDR3, the complementarity determining region (#3)

loop in Ig and TCRs that form the center of the antigen binding site and is highly variable in TCR
povides most of the antigen specificity

CD4 Co-receptor Molecule

a single chain molecule with 4 extracellular Ig type domains and linked intracellularly to Tyr kinase Lck

distinctive of Helper T Cells and have two populations

(1) Th-1 cells that Þ activated macrophages and Cytotoxic (CD8⁺) T cells

(2) Th-2 cells Þ conversion of B cells into antibody producing Plasma Cells

binds MHC II only and Ý affinity of TCR for MHC II on APC

CD8 Co-receptor Molecule

an a b heterodimer covalently associated by a disulfide bond

distinctive of Cytotoxic Tcells and facilitates stabilization of interaction of T Cell with MHC I APCs by binding MHC I

Superantigen

Activates a large number of helper T cells because it binds the Vb Domain of TCR out side the antigen specific site without being processed by APC

Similarities among TCR and Ig:

(1) coded for by genes that are rearranged by V, D, J, and C regions to increase diversity

(2) each is unique to its own cell until activated, at which point each is clonally expanded

Differences between TCR and immunoglobulins:

(1) TCR has 2 chains instead of 4

(2) TCR recognizes antigen in conjunction with MHC, whereas immunoglobulins recognize free antigen

Molecules of Antigen Recognition

T cell antigen receptor complex

T cell antigen receptor chains (TCR):

resemble membrane assoc. Fab fragment of Ig (heterodimers of two polymorphic molecules)

has extracellular part, transmembrane part, but no intracellular part Þ no siganal transduction

responsible for recognition of antigen

a /b heterodimer found on 90-95% of T cells in peripheral blood and spleen

g /d heterodimer found on CD4^-andCD8^- cells in peripheral blood (5-10%) – more abundant in mucosal epithelium

CD3: expression defines T cells – non-covalently associated with TCR but does not influence specificity

responsible for signal transduction following antigen binding to TCR
presence necessary for the expression of TCR

co-receptors of antigen recognition

CD4: expressed on subset of a/b cells (50-70%), mostly exclusive of CD8

binds to nonpolymorphic region on MHC class II; also binds to gp 120 on HIV virus

CD4 is associated with cells that produce large amounts of cytokines when activated Þ inflammation

noncovalently associated with intracellular molecule, protein kinase p56-lck

CD8: expressed almost exclusive of CD8 on 30-50% of T cells

binds MHC class I at a 3 nonpolymorphic region

associated with cells which mediate cytotoxic responses

noncovalently associated with intracellular molecule, protein kinase p56-lck

T lymphocyte co-stimulatory molecules – do not recognize antigen; binding influences activation event

CD2: expressed on all T cells, NK cells, thymocytes

adhesion molecule (i.e. binds to antigen presenting cell to facilitate antigen recognition)
ligands: CD58 (hematopoietic and non-hematopoietic cells); CD48 (most leukocytes); CD59 (T cells)
ligation enhances activation (proliferation and cytokine release) through adhesion and possibly other mechansims

CD28: expressed on T cell subsets, activated B cells

ligands: CD80(B7-1), CD86(B7-2) on B cells, monocytes, dendritic cells

expression of CD28 is enhanced after the T cell is activated through the TCR

ligation enhances release of IL-2 through cyclosporin A resistant pathway

CsA is normally used to inhibit IL-2 (i.e. transplant immunosupression)

Þ must depress B7-1 and B7-2 during transplant therapy

Þ increasing B7-1 and B7-2 can enhance the immune response to tumors

CD45: expressed on all hematopoietic cells

differential exon usageÞ CD45RA (expressed on naïve T cells); CD45RO (expressed on memory T cells)

possesses enzymatic activity, protein tyrosine phosphatase

associates with CD4 and CD8; necessary for signal transduction through TCR

CD5: expressed on B cells that produce autoantibodies; in children; in leukemia

ligand is CD72 on B cells

CD7: expressed on NK cells; early marker of T cells

CD40: expressed on B cells, monocytes, dendritic cells, vascular endothelial cells, fibroblasts

ligand: CD40L (CD40 ligand) also known as CD154

CD40L is found on activated T cells Þ communication between T and B, monocytes, dendritic

ligation on B cells Þ proliferation and IgE and IgG production

ligation on monocytes/dendritic cells Þ cytokine secretion (IL1, 6, ,8 10, 12, TNF-a )

mutation in CD154 Þ hyper-IgM syndrome (xs IgM, IgD; deficient IgG, IgE, IgA) – results in recurring bacterial infection

LFA-1: heterodimer of CD11a and CD18

ligand: ICAM1,2 (CD54, CD102) expressed on endothelial cells and inducible in most cells; also called rhinovirus receptor
ligation mediates cell-cell adhesion; enhances T cell activation
T cell activation enhances adhesion properties of LFA-1

Molecules of Homing

lymphocytes circulate in and out of blood 1-2 times per day

directed by active mechanisms of endothelial cells/T cell interactions, not random

(1) CD62L (L-selectin) on lymphocytes binding to CD34 (sialomucin) on endothelial cells as a primary adhesion factor for homing to lymph nodes (peripheral > mucosal)

(2) a integrins (CD49a-f; a4b7) on lymphocytes binding to MadCAM-1 on endothelial cells as a primary and secondary adhesion factor for homing to mucosal lymph nodes

(3) a integrins (CD49a-f; a4b1) on lymphocytes binding to VCAM-1 on endothelial cells as a primary and secondary adhesion factor for homing to extra-intestinal inflammatory sites

(4) cutaneous lymphocyte-assoc.antigen binding to E-selectin on endothelial cells as primary adhesion factor for homing to skin

(5) LFA-1 on lymphocytes binding to ICAM-1 on endothelial cells as a secondary adhesion factor for homing to tissues throughout body

(6) CD44 binding to hyaluronate as a primary adhesion factor for homing to inflammatory sites

(7) a integrins also mediate binding to laminin, collagen, and fibronectin in connective tissue