Impact of effector cell differentiation on CD4+ T cells that evade negative selection by a self-peptide

We have used a transgenic mouse system to examine how differing reactivities of TCRs expressed by naive versus effector cells can shape the functional potential of autoreactive CD4+ T cells. Transgenic mice expressing TCRs that exhibit either high (TS1) or low [TS1(SW)] reactivity toward the I-Ed-restricted determinant S1 from the influenza virus PR8 hemagglutinin (HA) were mated with transgenic mice expressing HA under the control of different promoters. HACII mice express HA driven by an MHC class II promoter, and both the TS1 and TS1(SW) TCRs underwent substantial deletion in this background. HA104 mice express HA driven by an SV40 promoter, and the highly reactive TS1 TCR was substantially deleted. By contrast, the less reactive TS1(SW) TCR underwent little or no deletion in TS1(SW) x HA104 mice, although CD5 up-regulation indicated that they had interacted with the S1 self-peptide. In adoptive transfer studies, naive CD4+ T cells expressing the TS1(SW) TCR failed to proliferate in response to the S1 peptide in HA104 mice, and were inefficient at providing help for HA-specific antibody responses. However, effector CD4+ T cells generated from TS1(SW) x HA104 mice acquired the ability to proliferate in response to the S1 peptide in HA104 mice, and were as efficient as CD4+ T cells expressing the high reactivity TS1 TCR in helping HA-specific antibody responses. Collectively, these studies demonstrate a basis by which CD4+ T cells expressing TCRs with low reactivity toward self-peptides can evade negative selection and acquire enhanced autoreactivity following activation by a cross-reactive antigen.