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Abstract
SummaryManipulating molecules that impact T cell receptor (TCR) or cytokine signaling, such as the protein tyrosine phosphatase non-receptor type 2 (PTPN2), has significant potential for advancing T cell-based immunotherapies. Nonetheless, it remains unclear how PTPN2 impacts the activation, survival, and memory formation of T cells. We find that PTPN2 deficiency renders cells in vivo and in vitro less dependent on survival-promoting cytokines, such as interleukin (IL)-2 and IL-15. Remarkably, briefly ex vivo-activated PTPN2-deficient T cells accumulate in 3- to 11-fold higher numbers following transfer into unmanipulated, antigen-free mice. Moreover, the absence of PTPN2 augments the survival of short-lived effector T cells and allows them to robustly re-expand upon secondary challenge. Importantly, we find no evidence for impaired effector function or memory formation. Mechanistically, PTPN2 deficiency causes broad changes in the expression and phosphorylation of T cell expansion and survival-associated proteins. Altogether, our data underline the therapeutic potential of targeting PTPN2 in T cell-based therapies to augment the number and survival capacity of antigen-specific T cells.
Highlights
Protein tyrosine phosphatase non-receptor type 2 (PTPN2) is a ubiquitously expressed tyrosine phosphatase found at high levels in resting and activated T cells (Tiganis and Bennett, 2007; Wiede et al, 2011)
We found that the complete absence of PTPN2 did not affect the principal ability to generate KLRG1+ effector and CD127+ memory T cells, but it delayed the decline of KLRG1+ T cells during the contraction phase and promoted their re-expansion capacity
PTPN2 Deficiency Promotes the Long-Term Maintenance of T Cells that Lack a Typical CD127+ Memory Phenotype To explore how PTPN2 impacts T cell differentiation, we took advantage of T cell receptor (TCR)-transgenic mice that develop MHC class Irestricted and ovalbumin-specific CD8+ T cells (OT-I T cells), in which the fifth exon of PTPN2 is flanked by LoxP sites (Loh et al, 2011)
Summary
Protein tyrosine phosphatase non-receptor type 2 (PTPN2) is a ubiquitously expressed tyrosine phosphatase found at high levels in resting and activated T cells (Tiganis and Bennett, 2007; Wiede et al, 2011). Genome-wide association studies (GWASs) raised particular interest in this molecule because loss-of-function single-nucleotide polymorphisms (SNP) in PTPN2 can confer a predisposition for the development of autoimmune diseases. These include type 1 diabetes (Burton et al, 2007; Todd et al, 2007), rheumatoid arthritis, Crohn’s disease, and celiac disease (Espino-Paisan et al, 2011; Festen et al, 2011; Smyth et al, 2008). PTPN2 deficiency in T cells leads to increased antigen sensitivity in vitro and in vivo This enhances the proliferative potential of T cells upon encountering antigen, as well as their capacity to undergo homeostatic proliferation, and favors the
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