The selection of effector T cell phenotype by contrasuppression modulates susceptibility to autoimmune injury

The genetic susceptibility to murine alpha TBM disease is a dominant trait that maps to H-2K. In previous studies we have shown that the critical difference between susceptible (SJL) and nonsusceptible (B10.S(8R] mice is the phenotype of the tubular Ag-specific effector T cells (TDTH). In SJL mice, these TDTH are Lyt-2+, whereas in B10.S(8R) mice the TDTH are L3T4+. These phenotypic differences have an important functional correlate: Lyt-2+ TDTH are nephritogenic, whereas L3T4+ TDTH are typically not nephritogenic. Both mouse strains have the potential to differentiate both L3T4+ and Lyt-2+ TDTH. The preferential selection of a single TDTH phenotype in each is the result of differential T cell regulation. In the present studies, we have examined the contribution of suppressor and contrasuppressor T cells in the regulation of TDTH phenotype selection. Our studies show that in both SJL and B10.(8R) mice, after exposure to Ag, a suppressor T cell subpopulation functions to inhibit the nephritogenic Lyt-2+ TDTH. In SJL, but not B10.S(8R) mice, this suppression is counterbalanced by Lyt-2+, Vicia Villosa lectin-adherent T cells. Such contrasuppressor function is mediated through a T cell-derived soluble protein (TcsF), which is Ag-binding and recognized by alpha I-JS antisera. This functional TcsF activity maps, as does susceptibility to disease, to H-2K. In the presence of genetically compatible TcsF, the TDTH phenotype in nonsusceptible mice switches to that of susceptible mice. These Lyt-2+ TDTH from nonsusceptible mice are fully capable of inducing tubulointerstitial nephritis following adoptive transfer. Our studies describe a new role for Tcs cells and augment our understanding of their etiopathogenetic role in autoimmunity.