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

Flosbach, Markus; Oberle, Susanne G; Scherer, Stefanie; Zecha, Jana; von Hoesslin, Madlaina; Wiede, Florian; Chennupati, Vijaykumar; Cullen, Jolie G; List, Markus; Pauling, Josch K; Baumbach, Jan; Kuster, Bernhard; Tiganis, Tony; Zehn, Dietmar

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.