Rac GTPases have opposite roles in T cells and dendritic cells in mucosal immune function (MUC8P.730)

Abstract

Variants in RAC1 and RAC2, which encode small Rho-family GTPases, are associated with risk for inflammatory bowel disease. We have shown reduced regulatory T-cell (Treg) proportions in Rac2 knockout (KO) mice with additional dendritic cells (DC)-specific deletion of Rac1compared to WT. Since Rac is crucial to TCR signaling, we hypothesized that a T-cell specific deletion of Rac1 would also result in defects in Treg development. Treg proportions and susceptibility to dextran sulfate sodium(DSS)-induced intestinal inflammation were assessed in mice deficient in Rac2 in addition to either T cell- or DC-specific deletion of Rac1 (cDKO). Surprisingly, elevated Treg proportions were observed in T-cell specific cDKO mice compared to WT as well as higher Treg proportions within the cDKO compared to the WT compartment in mixed bone marrow chimera. Furthermore, cDKO naïve CD4+ T cells were able to differentiate into Tregs, unlike cDKO DCs, which led to defective Treg generation of WT naïve CD4+ T cells in in vitro Treg generation assays. In vivo Treg generation was reduced in DC-specific cDKO mice compared to WT controls with ovalbumin (OVA) feeding following transfer of CD4+ T cells transgenic for OVA. Lastly, exacerbated DSS colitis was observed in DC-specific, but not T-cell specific cDKO mice, compared to WT. In conclusion, deficiency of Rac proteins result in contrasting effects on mucosal immune function in DCs compared to T cells. The precise mechanism is under investigation.