Protein Tyrosine Phosphatases: Regulators of CD4 T Cells in Inflammatory Bowel Disease

Abstract

Protein tyrosine phosphatases (PTPs) play a critical role in co-ordinating the signaling networks that maintain lymphocyte homeostasis and direct lymphocyte activation. By dephosphorylating tyrosine residues, PTPs have been shown to modulate enzyme activity and both mediate and disrupt protein-protein interactions. Through these molecular mechanisms, PTPs ultimately impact lymphocyte responses to environmental cues such as inflammatory cytokines and chemokines, as well as antigenic stimulation. Mouse models of acute and chronic intestinal inflammation have been shown to be exacerbated in the absence of PTPs such as PTPN2 and PTPN22. This increase in disease severity is due in part to hyper-activation of lymphocytes in the absence of PTP activity. In accordance, human PTPs have been linked to intestinal inflammation. Genome wide association studies (GWAS) identified several PTPs within risk loci for inflammatory bowel disease (IBD). Therapeutically targeting PTP substrates and their associated signaling pathways, such as those implicated in CD4⁺ T cell responses, has demonstrated clinical efficacy. The current review focuses on the role of PTPs in controlling CD4⁺ T cell activity in the intestinal mucosa and how disruption of PTP activity in CD4⁺ T cells can contribute to intestinal inflammation.

Keywords: CD4 T cells; JAK-STAT; cytokine; inflammatory bowel disease; protein tyrosine phosphatase.

Figure 1

The contribution of PTPs to CD4⁺ T cell activation and differentiation in colonic inflammation. IBD pathophysiology is associated with the disruption of the intestinal mucosal barrier due to genetic, environmental and/or immunological factors. Under such circumstances, an increase in the uptake and processing of luminal antigens by innate immune cells initiates and maintains the chronic inflammatory response characteristic of IBD. CD4⁺ T cells are activated in the mesenteric lymph nodes following recognition of their cognate antigen presented in the context of MHC on the surface of antigen presenting cells. Activated CD4⁺ T cells then enter the lamina propria from circulation and perpetuate inflammation, secreting pathogenic pro-inflammatory mediators and chemokines which recruit additional leukocytes. PTPs involved in the activation and/or differentiation of specific T cell subsets are indicated.

Figure 2

PTP regulation of antigen and cytokine receptor signaling. Schematic representation of signaling events regulated by PTPs discussed in the text. PTPs are linked to their respective substrates by a red bar-headed line. Dotted arrows depict translocation while solid black lines identify molecules linked in a signaling cascade. The direct interaction between STAT1 and PTPN11 models the sequestration of STAT1 from the IFNγR.

Figure 3

Classes of the tyrosine phosphatase family. (A) Sub-classes of Cys-based PTPs and the number of associated genes. (B) Representative PTPs from Class I Cys-based enzymes described in the review. (C) ASP-based PTPs. (D) His-based PTPs.