Immunotherapeutic implications of negative regulation by protein tyrosine phosphatases in T cells: the emerging cases of PTP1B and TCPTP.

In the context of inflammation, T cell activation occurs by the concerted signals of the T cell receptor (TCR), co-stimulatory receptors ligation, and a pro-inflammatory cytokine microenvironment. Fine-tuning these signals is crucial to maintain T cell homeostasis and prevent self-reactivity while offering protection against infectious diseases and cancer. Recent developments in understanding the complex crosstalk between the molecular events controlling T cell activation and the balancing regulatory cues offer novel approaches for the development of T cell-based immunotherapies. Among the complex regulatory processes, the balance between protein tyrosine kinases (PTK) and the protein tyrosine phosphatases (PTPs) controls the transcriptional and metabolic programs that determine T cell function, fate decision, and activation. In those, PTPs are de facto regulators of signaling in T cells acting for the most part as negative regulators of the canonical TCR pathway, costimulatory molecules such as CD28, and cytokine signaling. In this review, we examine the function of two close PTP homologs, PTP1B (PTPN1) and T-cell PTP (TCPTP; PTPN2), which have been recently identified as promising candidates for novel T-cell immunotherapeutic approaches. Herein, we focus on recent studies that examine the known contributions of these PTPs to T-cell development, homeostasis, and T-cell-mediated immunity. Additionally, we describe the signaling networks that underscored the ability of TCPTP and PTP1B, either individually and notably in combination, to attenuate TCR and JAK/STAT signals affecting T cell responses. Thus, we anticipate that uncovering the role of these two PTPs in T-cell biology may lead to new treatment strategies in the field of cancer immunotherapy. This review concludes by exploring the impacts and risks that pharmacological inhibition of these PTP enzymes offers as a therapeutic approach in T-cell-based immunotherapies.

The induction of SHP-1 degradation by TAOK3 ensures the responsiveness of T cells to TCR stimulation.

Thousand-and-one-amino acid kinase 3 (TAOK3) is a serine and threonine kinase that belongs to the STE-20 family of kinases. Its absence reduces T cell receptor (TCR) signaling and increases the interaction of the tyrosine phosphatase SHP-1, a major negative regulator of proximal TCR signaling, with the kinase LCK, a component of the core TCR signaling complex. Here, we used mouse models and human cell lines to investigate the mechanism by which TAOK3 limits the interaction of SHP-1 with LCK. The loss of TAOK3 decreased the survival of naïve CD4+ T cells by dampening the transmission of tonic and ligand-dependent TCR signaling. In mouse T cells, Taok3 promoted the secretion of interleukin-2 (IL-2) in response to TCR activation in a manner that depended on Taok3 gene dosage and on Taok3 kinase activity. TCR desensitization in Taok3-/- T cells was caused by an increased abundance of Shp-1, and pharmacological inhibition of Shp-1 rescued the activation potential of these T cells. TAOK3 phosphorylated threonine-394 in the phosphatase domain of SHP-1, which promoted its ubiquitylation and proteasomal degradation. The loss of TAOK3 had no effect on the abundance of SHP-2, which lacks a residue corresponding to SHP-1 threonine-394. Modulation of SHP-1 abundance by TAOK3 thus serves as a rheostat for TCR signaling and determines the activation threshold of T lymphocytes.