Identification of a locus on chromosome 1 regulating IL-17-producing γδ T cells and mortality after influenza infection.

Abstract

Abstract γδ T cells are an evolutionary conserved T cell subset with innate-like effector functions. We had previously identified a locus on chromosome 1 encompassing the Slam gene family that regulates the innate-like T cell compartment. To characterize this region further, we generated a B6.129 congenic mouse strain in which a 1.1 Mbp region (chr. 1: 171.05–172.12) from the 129X1/SvJ strain was introgressed onto the C57BL/6J background, and evaluated its effect on the host immune response in influenza-infected mice. Upon infection, we observed a significant and sustained increase in the number of lung γδ T cells in B6.129c2 congenic mice. A comparison of γδ T cell function revealed that a significantly greater fraction of B6.129c2 γδ T cells were producing IL-17A versus their B6 counterparts. These differences were subset-specific as they were observed in Vγ4 and at least one other Vγ subset, but not in Vγ1 T cells. Those IL-17-producing Vγ subsets accounted for most of the increase in B6.129c2 lung γδ T cell numbers and they displayed an attenuated cell surface expression profile of Slam family receptors. Finally, since enhanced IL-17 responses have been associated with immunopathology after influenza infection, we assessed the effect of the congenic interval on survival. We found that the survival of B6.129c2 congenic mice is significantly lower compared with B6 mice after influenza infection. Taken together, our data suggest that natural genetic variations at this locus significantly impact both IL-17A production by lung γδ T cells and mortality after influenza infection.