"A novel role for X-Chromosome Inactivation in regulating T cell responses to Influenza"

Katherine S. Forsyth and Montserrat C. Anguera

Women mount stronger immune responses during various infectious diseases, including influenza virus infections. Sexual dimorphism in immune responses to influenza has both hormonal and genetic origins, and the genetic contribution has not been investigated. The X chromosome contains many immunity-related genes important for T cell function, and X-linked gene expression is regulated through X-Chromosome Inactivation (XCI). While XCI maintenance is a static process in most somatic cells, mature T cells unusually display a 'dynamic’ mechanism of XCI maintenance, where Xist RNA clouds and repressive histone modifications become localized to the Xi upon stimulation. Here, we hypothesized that perturbations with XCI maintenance in T cells will affect T cell function and responses to influenza infection. Using a novel mouse model where Xist is specifically deleted in T cells (CD4cre+ Xistfl/fl mice), we demonstrate that perturbation of XCI maintenance in T cells results in enhanced protection from sublethal influenza challenge. While anti-influenza neutralizing antibody titers are comparable to controls, T cells in the lungs of CD4cre+ Xistfl/fl mice have elevated expression of the X-linked chemokine receptor CXCR3, a critical protein for effector T cell extravagation into the lungs. Intriguingly, we also found that CD4cre+ Xistfl/fl mice are more susceptible to a LD50 influenza challenge. Together, these data suggest that perturbation of XCI maintenance in T cells leads to heightened cellular functionality that is protective against low viral load but immunopathologic at high viral load. These data and ongoing experiments to further mechanistically characterize the X-linked genes involved in this phenotype will demonstrate, for the first time, that genetic contributions from the X play a role in sex differences with influenza infection and resulting disease pathologies.