Self-MHC restriction of the T cell receptor

Self-MHC restriction of TC cells

R. Zinkernagel & P. Doherty

Cloning of the TCR -chain gene by subtractive hybridization

By S. M. Hedrick &M. M. Davis

3 important assumptions made by Hedrick and Davis:

• The TCR mRNA would be associated with membrane-bound polyribosomes like the mRNAs that encode other integral membrane proteins. (eliminate ~97% mRNAs)

• 98% of the genes expressed in lymphocytes are common to B and T cells. TCR should be in the 2% genes expressed specifically in T cells. (DNA subtractive hybridyzation eliminates 98%)

• TCR genes should undergo DNA rearrangements like those observed in the Ig genes of B cells.

Structure of the T-cell receptor and surface IgM

Difference in the structures of the and receptors

Limited diversity

Organization of mouse TCR gene segments

A productive rearrangement of the chain gene segments deletes C

TCR variable- region genes rearrange in a manner similar to Ig gene

Junctional diversity

The CDR3 of the TCR has greater diversity than that seen in immunoglobulins

T-Cell Receptor Complex: TCR-CD3

CD3 is required for membrane expression of T cell receptors

or ζη

Structures of the CD4 and CD8 coreceptors

or dimer

CD8 binds to class I by contacting MHC class I 2 and 3 domains

CD4 binds to class II through MHC class II 2 and 2 domains

Affinity of TCR for peptide-MHC complexes is weak compared with antibody binding

T cell-APC interactions are strengthened by cell-adhesion molecules, including CD2, LFA-1, CD28, and CD45R

Role of coreceptors in TCR binding affinity

The ternary complexOf mouse TCRBound to MHCClass I and peptide

CDR3 CDR3

MHC molecule viewed from above

not in contact with peptide

CDR regions of mouse TCR and chains viewed from above

TCRs interact differently with class I and class II moleucles

Alloreactivity of T cells: in addition to self-MHC plus antigens, T cells also respond to foreign MHC molecules, a reaction that leads to rejection of allogeneic grafts (transplants in the same species)

Alloantigens: epitopes present on molecules that differ among members of the same species because of genetic variation.

T cells recognize a foreign MHC molecules directly. ~1-5% of all T cells are reactive to alloantigen.