T lymphocyte-specific deletion of SHPT and SHP2 promotes activation- induced cell death of CD4+T cells and impairs antitumor response

• 成果类型: Article
• 署名作者: Foster, Connor J. R.; Du, Jasper; Pundel, Oscar; Geer, Mitchell J.; Ripert, Ryan C.; Liu, Jia; Heim, Taylor A.; Araki, Kiyomi Y.; Lund, Amanda W.; Wang, Jun; Neel, Benjamin G.
• 署名单位: NYU Langone Medical Center; New York University; New York University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9621
• DOI: 10.1073/pnas.2427254122
• 发表日期: 2025-07-22
• 关键词: tyrosine-phosphatase; sh2 domain; fas antigen; thymocytes; tcr; expression; effector; pd-1; RECRUITMENT; dependence

摘要

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-specific single and double knockout mice, we found that SHP1 and SHP2 redundantly restrain na & iuml;ve 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+, but not CD8+, T cells lacking SHP1 and SHP2 show increased activation- induced cell death upon anti- CD3/CD28 stimulation. Adoptive transfer of antigen- specific CD4+ 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+ 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.