CD4+ T cells that evade deletion by a self peptide display Th1-biased differentiation

We have examined factors governing the differentiation of autoreactive CD4+ T cells that have evaded deletion by a self peptide. Two lineages of transgenic mice (HA12 and HA104) expressing the influenza virus hemagglutinin (HA) were mated with TS1 mice that express a clonotypic T cell receptor (TCR) specific for the I-Ed-restricted determinant site 1 (S1) of HA. Thymocytes expressing high levels of the clonotypic TCR were deleted in both TS1×HA transgenic lineages. However, through allelic inclusion, thymocytes expressing low levels of the clonotypic TCR and high levels of endogenous TCR α-chains evaded deletion in TS1×HA12 and TS1×HA104 mice to graded degrees. When stimulated with S1 peptide in vitro, the non-autoreactive TS1 T cells were biased toward differentiation into Th2 effectors. By contrast, CD4+ T cells that evaded deletion in TS1×HA12 and TS1×HA104 mice were progressively biased toward Th1-like differentiation. Moreover, the effector cells from TS1×HA12 and TS1×HA104 mice secreted higher levels of IFN-γ, on a per cell basis, than were secreted by their non-autoreactive counterparts. Thus, CD4+ T cells that evade deletion by a self peptide can exhibit an intrinsic bias toward differentiation into Th1 effector cells.