Modulation of TCR Signaling by Tyrosine Phosphatases: From Autoimmunity to Immunotherapy

Abstract

Early TCR signaling is dependent on rapid phosphorylation and dephosphorylation of multiple signaling and adaptor proteins, leading to T cell activation. This process is tightly regulated by an intricate web of interactions between kinases and phosphatases. A number of tyrosine phosphatases have been shown to modulate T cell responses and thus alter T cell fate by negatively regulating early TCR signaling. Mutations in some of these enzymes are associated with enhanced predisposition to autoimmunity in humans, and mouse models deficient in orthologous genes often show T cell hyper-activation. Therefore, phosphatases are emerging as potential targets in situations where it is desirable to enhance T cell responses, such as immune responses to tumors. In this review, we summarize the current knowledge about tyrosine phosphatases that regulate early TCR signaling and discuss their involvement in autoimmunity and their potential as targets for tumor immunotherapy.

SH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding

“…The role of the wild-type (WT) PTPN22/Csk complex in T-cell and other immune-cell signaling is not yet clear 32 . In some reports, binding to Csk appears to sequester and functionally suppress WT PTPN22, and the R620W variant is a gain-of-function allele 32 – 36 .…”

“…The role of the wild-type (WT) PTPN22/Csk complex in T-cell and other immune-cell signaling is not yet clear 32 . In some reports, binding to Csk appears to sequester and functionally suppress WT PTPN22, and the R620W variant is a gain-of-function allele 32 – 36 . Others have found the opposite, that the complex with Csk promotes PTPN22 function by colocalizing it with substrates 10 , 37 – 39 .…”

PP2A and Its Inhibitors in Helper T-Cell Differentiation and Autoimmunity

“…Protein phosphorylation is regulated by enzyme kinases and phosphatases, which catalyze phosphate’s addition or removal, respectively. The altered activity of these enzymes is one of the major defects in the development of various diseases, such as cancers, neurological and autoimmune disorders ( 1 – 3 ).…”

SH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding

“…The role of the wild-type (WT) PTPN22/Csk complex in T-cell and other immune-cell signaling is not yet clear 32 . In some reports, binding to Csk appears to sequester and functionally suppress WT PTPN22, and the R620W variant is a gain-of-function allele [32][33][34][35][36] .…”

“…The role of the wild-type (WT) PTPN22/Csk complex in T-cell and other immune-cell signaling is not yet clear 32 . In some reports, binding to Csk appears to sequester and functionally suppress WT PTPN22, and the R620W variant is a gain-of-function allele [32][33][34][35][36] . Others have found the opposite, that the complex with Csk promotes PTPN22 function by colocalizing it with substrates 10,[37][38][39] .…”