HLA-DR AND H-2E TRANSGENES DIFFERENTIALLY MEDIATE TCR-SPECIFIC POSITIVE SELECTION

The use of HLA transgenic mice in models of immunity and disease assum es that human MHC molecules are able to contribute toward the positive selection of the mouse TCR repertoire. As an initial step towards ana lysis of this we have compared the relative ability of DRalpha/Ebeta o r Ealpha/Ebeta complexes to induce T cell receptor (TCR) positive sele ction in H-2Ea and HLA-DRA transgenic mice lacking endogenous Ealpha. The results show that, like EalphaEbeta, the hybrid DRalpha/Ebeta comp lexes are capable of mediating positive selection of V(beta)2+, V(beta )6+, and V(beta)10+ cells. However, differences were found between the effects of the two transgenes Thus, while V(beta)6+ cells were effici ently selected in both H-2Ea and DRA transgenic mice, positive selecti on of V(beta)10+ cells was less apparent in the DRA transgenic mice Va riation between Ea and DRA transgenic mice is consistent with the noti on that this process is dependent on differential binding of endogenou s peptides to the Ealpha/Ebeta and DRalpha/Ebeta complexes. Furthermor e, contrary to expectations, in neither set of mice was positive selec tion limited solely to the CD4+ subset. Thus, examples were found in w hich V(beta)-specific positive selection was confined to either the CD 4+ or CD8+ subsets, and others in which both subpopulations were conco mitantly increased. In the case of V(beta)2 positive selection, H-2Ea transgenic mice showed expansion of these cells in both the CD4+ and C D8+ subpopulations while in DRA transgenic mice this occurred predomin antly in the CD8+ subpopulation.