Antigen-specific recognition is critical for the function of regulatory CD8(+)CD28(-) T cells.

The immunomodulatory properties of CD8 T cells with regulatory phenotype have become evident. It remains unclear whether the immunomodulatory function of CD8(+)CD28(-) T cells requires antigen-specific TCR interaction with major histocompatibility complex class I (MHC I). We have isolated naïve CD8(+)CD28(-) T suppressor cells (Tsup) from H2-Kk Des-TCR mice that express a transgenic, MHC class I-restricted, clonotypic TCR against an allogeneic MHC class I molecule (H2-Kb) plus self-peptide. These cells were compared to B10.BR wild type (w/t) CD8(+)CD28(-) T cells and to naïve CD4(+)CD25(+) regulatory T cells (Treg) of the same strains. Des CD8 effector T cells proliferated more readily when stimulated by H2-Kb splenocytes than w/t controls, whereas Des CD4 T cells showed the same alloresponse as w/t cells. Activation and proliferation of B10.BR CD4 T cells stimulated by H2-Kb APC were suppressed more effectively by Des CD8(+)CD28(-) T cells than by w/t CD8(+)CD28(-) T cells. On the contrary, Des CD4(+)CD25(+) T cells inhibited T cell proliferation less effectively than w/t CD4(+)CD25(+) T cells. In conclusion, we demonstrate that the function of naive Tsup is strongly enhanced by antigen recognition. Therefore we expect that Tsup are possible candidates for antigen-specific immunosuppressive therapy.