Contribution of Innate-like Tregs for Preventing Tissue Inflammation

Abstract Summary for administrative supplement: Based in part our studies performed under the parent R01, we now recognize that subpopulations of T cells have distinct, innate-like effector functions that lead to the modification of other immune cells. These effector functions are directly enabled by master regulator BTB-ZF transcription factors. PLZF (ZBTB16) expressing natural killer T cells, for example, continuously produce IL-4, which directly impacts the function of naïve CD8 T cells. The innate-like Tregs identified by our current studies, impact tissue homeostasis and macrophage function by the continuous release of IL-10. Our most recent studies have identified yet another BTB-ZF gene that we hypothesize controls the function of subsets of human CD8 T cells. Experiments proposed in this administrative supplement will analyze lymphocytes expressing these transcription factors in the response to SARS-CoV-2. Fatal infection is hypothesized to be a consequence of an inadequate innate immune response. In contrast, the devasting cytokine storms that lead to multiorgan inflammatory syndrome (MIS) are considered to be due, at least in part, to an overzealous innate immune response. The participation of innate-like lymphocytes has not yet been considered or evaluated.