Ptpn2 and KLRG1 regulate the generation and function of tissue-resident memory CD8+ T cells in skin

Katharina Hochheiser, Florian Wiede, Teagan Wagner, David Freestone, Matthias H. Enders, Moshe Olshansky, Brendan Russ, Simone Nüssing, Emma Bawden, Asolina Braun, Annabell Bachem, Elise Gressier, Robyn McConville, Simone L. Park, Claerwen M. Jones, Gayle M. Davey, David E. Gyorki, David Tscharke, Ian A. Parish, Stephen TurnerMarco J. Herold, Tony Tiganis, Sammy Bedoui, Thomas Gebhardt

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Abstract

Tissue-resident memory T cells (TRM cells) are key elements of tissue immunity. Here, we investigated the role of the regulator of T cell receptor and cytokine signaling, Ptpn2, in the formation and function of TRM cells in skin. Ptpn2-deficient CD8+ T cells displayed a marked defect in generating CD69+ CD103+ TRM cells in response to herpes simplex virus type 1 (HSV-1) skin infection. This was accompanied by a reduction in the proportion of KLRG1 memory precursor cells and a transcriptional bias toward terminal differentiation. Of note, forced expression of KLRG1 was sufficient to impede TRM cell formation. Normalizing memory precursor frequencies by transferring equal numbers of KLRG1− cells restored TRM generation, demonstrating that Ptpn2 impacted skin seeding with precursors rather than downstream TRM cell differentiation. Importantly, Ptpn2-deficient TRM cells augmented skin autoimmunity but also afforded superior protection from HSV-1 infection. Our results emphasize that KLRG1 repression is required for optimal TRM cell formation in skin and reveal an important role of Ptpn2 in regulating TRM cell functionality.

Original languageEnglish
Article numbere20200940
Number of pages21
JournalJournal of Experimental Medicine
Volume218
Issue number6
DOIs
Publication statusPublished - 29 Apr 2021

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