Ptpn22 Modifies Regulatory T Cell Homeostasis via GITR Upregulation

The Journal of Immunology : Official Journal of the American Association of Immunologists
Dominika J Nowakowska, Stephan Kissler

Abstract

PTPN22 gene variation associates with multiple autoimmune diseases, including type 1 diabetes and rheumatoid arthritis. Loss of function studies have demonstrated that PTPN22 impinges on the homeostatic behavior of regulatory T (Treg) cells, a lineage critical for immune tolerance. The frequency and absolute number of Treg cells is increased in Ptpn22-deficient mice, but the mechanism driving this increase is unknown. In this study, we show that Ptpn22 knockdown (KD) promoted the expansion of the Treg cell compartment by upregulating the glucocorticoid-induced TNFR family-related protein (GITR) and increasing GITR signaling. Ptpn22 KD did not accelerate cell division but instead prolonged Treg cell survival, as measured by a decrease in the frequency of apoptotic Treg cells. Loss of Ptpn22 caused a concomitant increase in the proportion of CD44(hi)CD62L(lo) effector Treg cells, at the expense of CD44(lo)CD62L(hi) central Treg cells. The increase in Treg cell numbers, but not their differentiation toward an effector phenotype, was dependent on GITR signaling, because blockade of GITR ligand prevented Treg cell expansion caused by Ptpn22 KD. These findings indicate that GITR plays a key role in regulating the overall size of the ...Continue Reading

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Citations

Mar 10, 2017·Nature Reviews. Rheumatology·Michael Croft, Richard M Siegel
Sep 29, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Lillian SeuOlaf Kutsch
Jan 7, 2018·Clinical Science·Shu-Han YangZhe-Xiong Lian
Sep 7, 2017·Immunology and Cell Biology·Emma M CarringtonAndrew M Lew
May 17, 2017·The Journal of Experimental Medicine·Victoria S PellyMark S Wilson
May 18, 2019·Current Pharmaceutical Biotechnology·Bednarczyk MartynaJanikowska Grażyna
Jan 31, 2017·Journal of Clinical Medicine·Jason S Ellis, Helen Braley-Mullen
Nov 10, 2020·Frontiers in Immunology·Jie TianShengjun Wang
Mar 16, 2021·Frontiers in Immunology·Lucas H ArmitageClayton E Mathews
Aug 22, 2021·The Journal of Biological Chemistry·Hanzeng LiGail A Bishop

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