Functional analysis of Qa-1, a ligand involved in both innate and adaptive immune responses.

摘要

Qa-1 is an MHC class Ib molecule that is recognized by CD94/NKG2 family members, which represent one of a number of families of NK cell receptors. Inhibition of NK cell cytotoxicity via CD94/NKG2A, an inhibitory family member, has been shown to be dependent on Qa-1 presenting its dominant peptide, Qdm, which is derived from the leader sequence of many MHC class la molecules. In chapter 1 we demonstrate that Qa-1 recognition by CD94/NKG2A and by CD941NKG2C, a putative activating receptor, is peptide specific, recognition being highly dependent on the amino acid residue at position 8 within the peptide bound to Qa-1. Qa-1 has also been shown to present a peptide from S. typhimurium GroEL, which is conserved within many Gram negative bacteria, and the corresponding peptide from the homologous murine protein, hsp60. Here we demonstrate that the GroEL and hsp60 peptides are not able to inhibit NK cell lysis at 10mM concentration.; In chapter 2 the hsp60 peptide is identified as the dominant Qa-1 binding peptide in the absence of Qdm. This hsp60 peptide and the corresponding peptide from S. typhimurium GroEL enable a Qa-1 restricted alloreactive CD8+ T cell clone to recognize Qa-1, further verifying that both of these peptides bind to Qa-1.; The second distinct receptor identified for Qa-1 is the αβ T cell receptor. In chapter 3 the role of Qa-1 in lymphocyte development and in the immune response to S. typhimurium is assessed by expressing Qa-1 as the only MHC class I molecule on the surface of cells by expressing Qa-1 as a transgene fused to β₂-microglobulin, on a β ₂-microglobulin deficient background. The transgenic version of Qa-1 does not alter TCRαβ+ CD8+ T cell development but it does allow for the expansion of a novel, hither to not described TCRγδ+ CD8αβ+ CD94− T cell population in the IEL of the intestine, in response to intra-peritoneal infection with an avirulent strain of S. typhimurium.