Cell Biology Lecture 39 Notes p.1246-1251 T Cell Selection
95% of T cells not useful. Must recognize "self", not too tightly.
Put "Y" thymus into "X" mouse + bone marrow, get T cells specific
for "Y" MHC + foreign Ag (not "X" MHC).
Transgenic mouse; known alpha-beta TCR (all cells=same spec.)
suppresses native TCR formation. Thymus cells must have right MHC,
or, T cells die.
Tc recognize class I, Th recognize class II in thymus. No ClassI in
thymus, no Tc cells. No classII in thymus; no Th cells.
If TCR binds self peptide + self MHC, neg.selection (no autoimm.)
Options: 1.Bind strongly to MHC-peptide in thymus; dead 2.Bind
weakly to MHC-peptide in thymus; positive selection 3.Don't bind at all to MHC peptide in thymus; dead (clonal anergy)
Evidence: TCR for male-specific peptide proliferate in female only.
Positive selection on epithelial cells (signal survival to weak-bound; negative on APC (from marrow, apoptosis). Both;Class I, II
Some anti-self eliminated after thymus. Some made anergic.
History: MHC discovery; graft rejection (H2 incompatible; class I), some inbreds don't respond to simple antigens (Ir genes; class II).
Also, if self MHC + foreign peptide look like self MHC+ self, no T cells left to respond to self + foreign peptide.
Why are T cells so alloreactive? Foreign MHC + self Ag looks like self MHC + foreign Ag to lots of Tc cells.
Why MHC alleles so polymorphic? React to altered pathogen surfaces. Also why heterozygotes favored; 2 chances to make MHC molecule.
Evidence: anti-malarial MHC molecule in 25% of West Africans.
Why not more MHC loci, diversity? Add more of these, fewer useful T cells.
Ig superfamily members: antibodies, TCR, MHC, CD4, CD8, CD28,invariant associated with B,T receptors, Fc receptors. 40% of polypeptides on WBC
Ig superfamily arose more than 400 x 106 years ago. Some invertebrates have primitive Ig-like molecules