T Cell Homeostasis

Summary The durability of diverse forms of T cell memory is critical for effective immunity against various pathogens, and can be harnessed for cancer immunotherapy. Yet the signals that maintain T cell memory, and preserves the identity of distinct memory subsets, are incompletely understood. In particular, while there is considerable data suggesting that the cytokines IL-7 and IL-15 are important for preservation of memory CD8+ T cells, there are discrepancies in the literature that suggest this does not apply to all subpopulations of memory cells, or to all infectious systems. We believe some of these discrepancies arise from experimental procedures that do not accurately evaluate established memory T cell homeostasis (but which are conditioned by effects on memory generation). To test this, in Aim 1, we will use temporally inducible gene knockout strategies to eliminate sensitivity of T cells to IL-7 and/or IL-15, after the memory populations have been generated. We will examine these models in both steady-state T cell homeostasis and in the response to “bystander” infections. In Aim 2, we investigate the stability of two major classes of memory T cells – recirculating memory cells (“TMM”) and tissue-resident (“TRM”) cells. Each has different functional roles and distinct trafficking patterns. Based on published and preliminary studies, we will explore the role of the transcription factor KLF2 in controlling the “identity” of TMM vs TRM (and whether changes in KLF2 expression – by genetic manipulation or in response to statin drugs - will cause interconversion of TRM and TMM). We also investigate novel findings which indicate that expression of the egress factor S1PR1 (which is a gene regulated by KLF2) is critical for recirculation of TMM produced following some infections but not others, with consequences for therapeutic strategies to restain pathogenic T cell responses by targeting S1PR1. Again, these models will harness inducible gene knockout/expression models, as well as pharmacological treatments. Together, these studies represent a novel and highly significant investigation into the basis for durability in the diverse subpopulations of memory CD8+ T cells, with implications for how this can be manipulated for therapeutic goals.