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.