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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,7,22]]},"abstract":"<jats:p>\n                    SHP1 (PTPN6) and SHP2 (PTPN11) are closely related protein-tyrosine phosphatases (PTPs), which are autoinhibited until their SH2 domains bind paired tyrosine-phosphorylated immunoreceptor tyrosine-based inhibitory\/switch motifs (ITIMs\/ITSMs). These PTPs bind overlapping sets of ITIM\/ITSM-bearing proteins, suggesting that they might have some redundant functions. By studying T cell\u2013specific single and double knockout mice, we found that SHP1 and SHP2 redundantly restrain na\u00efve T cell differentiation to effector and central memory phenotypes, with SHP1 playing the dominant role. Surprisingly, loss of SHP2 alone in T cells enhanced the antitumor effects of anti-PD-1 antibodies, whereas there was no effect of SHP1 deletion. Also unexpectedly, the absence of both PTPs resulted in poorer tumor control and failure to respond to Programmed Cell Death Protein 1 (PD-1) blockade, associated with reduced frequency and activation of T cells and dendritic cells. Mechanistic studies revealed that CD4\n                    <jats:sup>+<\/jats:sup>\n                    , but not CD8\n                    <jats:sup>+<\/jats:sup>\n                    , T cells lacking SHP1 and SHP2 show increased activation-induced cell death upon anti-CD3\/CD28 stimulation. Adoptive transfer of antigen-specific CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells restored normal levels of tumor control in mice lacking both PTPs. Together, our results demonstrate that SHP1 or SHP2 is required to prevent activation-induced cell death of CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and is critical for tumor immunity, raising the possibility that inhibition of SHP2 might augment the therapeutic efficacy of PD-1-based immune therapy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2427254122","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T19:01:31Z","timestamp":1752519691000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":9,"title":["T lymphocyte\u2013specific deletion of SHP1 and SHP2 promotes activation-induced cell death of CD4\n                    <sup>+<\/sup>\n                    T cells and impairs antitumor response"],"prefix":"10.1073","volume":"122","author":[{"given":"Connor J. 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