Hypoxia Acts As An Environmental Cue For The Human Tissue-Resident Memory T-Cell Differentiation Program

<p>Tissue-resident memory T-cells (T_RM) 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 T_RM 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<em> </em>led to the development of a T_RM phenotype, characterized by a greater than five-fold increase in CD69+CD103+ cells expressing human T_RM hallmarks and enrichment for endogenous human T_RM 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 T_RM 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 T_RM differentiation program. Our findings identify a previously unreported cue for the T_RM differentiation program, and can enable facile generation of human T_RM phenotype cells in vitro<em> </em>for basic studies and translational applications such as adoptive cellular therapy.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2021

Authors dc:creator

• Hasan, Farah
• <p><a href="http://www.orcid.org/0000-0001-6941-7822" target="_blank" title="http://www.orcid.org/0000-0001-6941-7822 ">0000-0001-6941-7822</a></p>

Contributors dc:contributor

• Cassian Yee
• Michael Curran
• Matthew Gubin

• hypoxia
• TGF-beta
• T-cells
• tissue-resident memory
• Immunology and Infectious Disease
• Immunotherapy

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1109

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2166