Flosbach and Oberle et al. demonstrated that loss of PTPN2 led to increased programmed expansion of KLRG+CD127- T cells with a non-conventional, but functionally memory phenotype, without affecting T cell development, effector function, or memory formation. Loss of PTPN2 delayed contraction of and/or increased secondary expansion of KLRG1+ T cells. Briefly ex vivo-activated PTPN2-deficient cells accumulated 11 times higher in blood in antigen-free hosts. PTPN2 loss altered the cytokine signal transduction in activated T cells, increased sensitivity to IL-2, and decreased dependence on pro-survival signals.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany. (2) Division of Immunology and
Author Info: (1) Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany. (2) Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland. (3) Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany; Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland. (4) Chair of Proteomics and Bioanalytics, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany. (5) Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany. (6) Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (7) Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland. (8) Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany. (9) Big Data in BioMedicine Group, Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany. (10) ZD.B Junior Research Group LipiTUM, Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany. (11) Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany. (12) Chair of Proteomics and Bioanalytics, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany. (13) Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. (14) Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany; Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland. Electronic address: dietmar.zehn@tum.de.
