Effect of neo-self-expression of hemagglutinin (HA) in shaping the peripheral T cell repertoire and response to MHC class II restricted determinants of HA

The effect of neo-self expression of the influenza virus PR8 hemagglutinin (PR8 HA) in shaping the peripheral T cell repertoire and response was examined using two lineages of HA transgenic mice. HA$\sb{\rm memb}$ mice express the entire viral HA as a membrane-bound antigen, whereas HA$\sb{\rm trunc}$ mice express lower levels of a truncated HA polypeptide. The ability of HA$\sb{\rm trunc}$ and HA$\sb{\rm memb}$ mice to mediate negative selection to two individual MHC class II-restricted T cell determinants from the HA was assessed by the induction of HA-specific T cells during a viral infection and by the generation of TCRxHA mice. HA$\sb{\rm trunc}$ and HA$\sb{\rm memb}$ mice were analyzed for their ability to generate T cell responses to the major I-E$\sp{\rm d}$-restricted and I-A$\sp{\rm d}$-restricted determinants from the HA (designated S1 and S2, respectively). By both approaches, it was found that HA$\sb{\rm memb}$ mice mediate more efficient negative selection of autoreactive T cells than do HA$\sb{\rm trunc}$ mice, suggesting the extent of negative selection is dose dependent. Of the two major MHC class II determinants, S1-specific T cells were found to be more effectively eliminated than are S2-specific T cells. Results from thymocyte suspension cultures suggest differences in the efficiency of peptide presentation resulted in differences in that the extent of negative selection of HA-specific T cells. Neo-self expression of HA resulted in alterations in the subsequent effector population and functions. S1-specific T cells from TS1xHA mice expressed lower levels of S1-specific TCR and expressed the inappropriate (CD8) or neither coreceptor. S1-specific T cells from both TS1xHA mice were functionally compromised, requiring IL-2, IL-4, or IL-12 to differentiate into effector cells. Moreover, TS1xHA$\sb{\rm memb}$ cells failed to proliferate and to secrete IL-2 and IL-4 upon restimulation. TS1xHA$\sb{\rm trunc}$ cells proliferated and secreted cytokines to an intermediate level between that of TS1 and the TS1xHA$\sb{\rm memb}$ effectors. Differentiation into IFN-$\gamma$ producing, cytolytic effectors was preserved in cells from both lineage. Together, the findings demonstrate that differences in the form, dose and determinant can shape the composition and effector function of autoreactive T cells