Regulatory T cell coordination of the mucosal NK cell response during viral infection.

Abstract

Abstract In many infections the mucosal barrier is the site of pathogen exposure, yet the regulation of mucosal immunity is not well understood. Herpes simplex virus-2 (HSV-2) is one of the most prevalent mucosal infections, making this disease an ideal model to study mucosal anti-viral immune response. My goal is to define how regulatory T cells (Tregs) shape anti-viral immune responses through modulation of natural killer (NK) cells during mucosal virus infection. To accomplish my goal, I utilized a mouse model of intravaginal HSV-2 infection. NK cell phenotypes were examined using high parameter flow cytometry. To define how transient Treg depletion during HSV-2 infection impacts NK cells, I utilized Foxp3DTR mice. Treg depletion led to increased maturation of NK cells in the vaginal tract (VT). KLRG1 is associated with NK cell maturation and is a marker of terminally mature NK cell subsets. I found a significant increase in the frequency and total number of KLRG1+ NK cells in the VT two days after HSV-2 infection in the absence of Tregs. I further analyzed NK cell maturation using the expression of the two surface markers CD11b and CD27 and found a significant increase in CD11b+CD27+ NK cells after Treg depletion. This subset of NK cells is known to be significant producers of pro-inflammatory cytokines. The cytokine IL-15 is necessary for NK cell development and maturation. I found that in the VT, CD11b+Ly6C+ monocyte-derived DCs display increased IL-15 transpresentation after Treg depletion. My data suggests that Tregs have a modulatory effect on NK cell development in the VT as Treg depletion leads to altered NK cell maturation and development. This demonstrates the role of Tregs in mediating an effective immune response while limiting immune pathology. Supported by grants from NIH (R01 AI141435-01, T32 AI 7509-21)