Regulatory T cells (Treg) play an important role in controlling pathology caused by excessive inflammatory or autoimmune responses. We have discovered a novel population of unconventional, innate-like PLZF+TCRaß+CD8aa+ T cells, named CD8aa Tunc, in naïve mice and in healthy humans that are distinguishable from the conventional CD8 T cells by PLZF expression and innate markers. Notably, adoptive transfer of sorted CD8aa Tunc but not conventional CD8 T cells protect mice from T cell-mediated autoimmune inflammatory diseases. A major portion of CD8aa Tunc is restricted by a non-classical MHC molecule, Qa-1b and accordingly, a CD11c+CD44+CD122+Ly-49+ subset controls autoimmunity in a Qa-1b–dependent manner. Furthermore, using a peptide library, we have identified a potent Qa-1-binding peptide that is recognized by CD8aa Tunc. Importantly, activation/expansion of CD8aa Tunc with the agonist peptide regulate not only conventional T cell- but also innate cell-mediated autoimmune diseases. Our central hypothesis is that CD8aa Tunc play an important role in controlling inflammation in kidney and accordingly, they are either significantly reduced in lupus-prone BXSB-Yaa mice or are defective in NZBWF1 mice. In Aim 1, we would like to test the hypothesis that CD8aa Tunc in NZBWF1 mice have a unique transcriptional signature different from that in B6 mice and from the non-regulatory CD8 T cells. In Aim 2, we would like to test the hypothesis that peptide-induced activation/expansion of CD8aa Tunc control lupus nephritis in NZBWF1 mice by inhibiting inflammatory T follicular helper (Tfh) cells and type I IFN-secreting pDCs. Collectively, the proposed studies will set an important foundation for understanding how regulatory CD8aa Tunc maintain tolerance in kidney tissue and also will have important implications for targeting conserved HLA-E-binding peptide-based novel therapeutic approach in lupus nephritis.