Hypoxia Acts as an Environmental Cue for the Human Tissue-Resident Memory T-cell Differentiation Program
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Date of Graduation
Doctor of Philosophy (PhD)
Tissue-resident memory T-cells (TRM) provide frontline defense against viral diseases and can contribute to anti-tumor immunity; however, aside from the necessity of TGF-β, little is known regarding cues for TRM differentiation. Oxygen tension is an environmental cue that distinguishes peripheral tissues from the circulation and here, we demonstrate that differentiation of human CD8+ T-cells under hypoxic conditions in the presence of TGF-β1 led to the development of a TRM phenotype, characterized by a greater than five-fold increase in CD69+CD103+ cells expressing human TRM hallmarks and enrichment for endogenous human TRM gene signatures, including increased expression of adhesion molecules and decreased expression of genes involved in recirculation. Hypoxia and TGF-β1 synergized to produce a significantly larger population of TRM phenotype cells than either condition alone, and comparison of these cells from the individual and combination conditions revealed distinct phenotypic and transcriptional profiles, indicating a programming response to environmental cues rather than a mere expansion. These observations suggest that lower oxygen tensions such as those found in peripheral tissues, sites of inflammation, and tumors, can promote the TRM differentiation program. Our findings identify a previously unreported cue for the TRM differentiation program, and can enable facile generation of human TRM phenotype cells in vitro for basic studies and translational applications such as adoptive cellular therapy.
hypoxia, TGF-beta, T-cells, tissue-resident memory