PTPN2 Deficiency Enhances Programmed T Cell Expansion and Survival Capacity of Activated T Cells

Abstract

Summary Manipulating 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.

Ptpn2 and KLRG1 regulate the generation and function of tissue-resident memory CD8+ T cells in skin

“…Furthermore, single-nucleotide polymorphisms in the human PTPN2 gene have been linked to development of autoimmunity and chronic inflammatory disorders in patients ( Todd et al, 2007 ; Smyth et al, 2008 ). Consistent with its molecular function in attenuating TCR and cytokine receptor signaling ( Aoki and Matsuda, 2002 ; Simoncic et al, 2002 ; ten Hoeve et al, 2002 ; Wiede et al, 2014a ; Wiede et al, 2011 ), Ptpn2 has previously been shown to restrain CD8 + T cell responses to self-antigen, tumors, and acute and chronic systemic infections, although recirculating memory CD8 + T cells can from normally after acute bacterial infection in absence of Ptpn2 ( LaFleur et al, 2019 ; Wiede et al, 2014a ; Wiede et al, 2020 ; Wiede et al, 2011 ; Wiede et al, 2014b ; Flosbach et al, 2020 ). We describe a similar function of Ptpn2 in regulating effector CD8 + T cell differentiation during an acute virus infection of skin.…”

“…The surface molecules CD127 (IL-7Rα) and KLRG1 are often used as markers to predict the memory potential of activated CD8 + T cells, with short-lived effector cells identified as CD127 lo KLRG1 + and long-lived memory precursors as CD127 hi KLRG1 − cells ( Joshi et al, 2007 ; Sarkar et al, 2008 ), the latter of which also contain cells that can give rise to CD69 + CD103 + T RM cells ( Mackay et al, 2013 ; Sheridan et al, 2014 ). Given that Ptpn2 has recently been identified as a regulator of CD8 + T cell expansion and differentiation during systemic infection ( LaFleur et al, 2019 ; Flosbach et al, 2020 ), we next compared the phenotype of effector T cells arising in the presence or absence of Ptpn2 expression around the peak of expansion after acute peripheral infection. Flow cytometric analysis of OT-I cells isolated from spleens 9 d after HSV single or double infection revealed a marked reduction in the frequency of KLRG1 – and CD127 hi memory precursors among Lck -Cre; Ptpn2 fl/fl cells when compared with Ptpn2 fl/fl controls ( Fig.…”

“…In these experiments, Ptpn2-deficient KLRG1 − effector cells actually generated more memory T cells in spleen than their WT counterparts, which is in line with a recent report showing superior engraftment after i.v. transfer of briefly in vitro–stimulated CD8 + T cells in absence of Ptpn2 ( Flosbach et al, 2020 ). Both observations may be explained by increased proliferative momentum of activated Ptpn2-deficient cells before transfer, which is also echoed by our combined transcriptional and GO analyses, as well as to their heightened responsiveness to cytokines known to promote the survival and homeostatic turnover of recirculating memory T cells, such as IL-7 and IL-15.…”

Combination Approaches to Target PD-1 Signaling in Cancer

“…PTPN2 also helps control the T cell activation threshold by dephosphorylating SRC family kinases necessary for functions downstream of TCR ligation ( 73 , 84 ). Studies in vitro and in vivo in mice have shown that deletion of PTPN2 in T cells results in enhanced CD8 T cell proliferation and survival, with decreased dependency on pro-survival cytokines like IL-2 and IL-15 ( 85 ).…”

T Cell Protein Tyrosine Phosphatase in Osteoimmunology

“…Undoubtedly, T cells play a critical role in bone homeostasis, wherein the effects of TCPTP on T cell function cannot be neglected ( Figure 2C ). TCPTP negatively regulates T cell activation ( 94 , 95 ). Tcptp −/− T cells show enhanced cell activity via the reduction of T cell receptor (TCR) threshold and hyperphosphorylation of the activated tyrosine residue of Lck ( 75 ).…”