title: Ptpn22 Modifies Regulatory T Cell Homeostasis via GITR Upregulation.
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 Treg cell pool. Our results suggest that the size and composition of the Treg cell compartment are independently controlled and have implications for the design of immunotherapies that seek to improve Treg cell function.
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Dominika J
authors.initials: DJ
authors.lastname: Nowakowska
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215 Stephan.Kissler@joslin.harvard.edu.
authors.forename: Stephan
authors.initials: S
authors.lastname: Kissler
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D055785:Gene Knockdown Techniques; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000276:immunology*; D006706:Homeostasis / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D053450:Glucocorticoid-Induced TNFR-Related Protein; C106544:Tnfrsf18 protein, mouse; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C516766:Ptpn22 protein, mouse
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