Peripheral Human Organs Harbor Distinct T$_{reg}$ Cell Subsets Exhibiting Tissue-Specific Adaptation Profiles

Abstract

In this thesis, to obtain insight into organ-specific adaptation programs of tissue-homing Treg cells, we performed single-cell RNA and T cell receptor sequencing coupled with high-dimensional flow cytometry in human blood, tonsil, mesenteric lymph node (mLN), colon, and skin samples. We found Treg cells carried distinct transcriptional and phenotypical characteristics in different organs. Treg cells in blood and tonsils exhibited intermediate interleukin-2 receptor  (also known as CD25) and CD39 and high levels of CD27. Conversely, mLN Treg cells showed the lowest CD39 expression. Both, blood and mLN Treg cells proliferated highly. Compared to blood, Treg cells in the colon showed very low levels of CD27 and higher levels of T-cell immunoreceptor with Ig and ITIM domains (TIGIT), Cytotoxic T-lymphocyte associated protein 4 (CTLA4) and tumor necrosis factor receptor superfamily member 9 (TNFRSF9, coding for 4-1BB), and expression of basic leucine zipper ATF-like transcription factor (BATF) and Krüppel-like factor 6 (KLF6). Colon Treg cells carried an interferon signature, were clonally distinct from Treg cells of other organs, and followed a colonic circular trafficking model. Skin Treg cells exhibited the highest levels of CD25 and CD39, were CD27high, and expressed BATF, KLF6, PRDI-BF1 and RIZ homology domain 1 (PRDM1, coding for Blimp-1) and Runt-related transcription factor 3 (RUNX3) alongside a gene signature of tissue repair. Moreover, we observed that organ-specific cytokine and metabolite milieus influenced the Treg cell transcriptomes.

Collectively, our results show that human Treg cells in peripheral tissues adopt distinct transcriptional programs in response to local cytokine and metabolite milieus. These findings provide important insights into tissue-resident Treg cells in humans and could guide future efforts to target these Treg cell subsets in a selective manner.