Regulation of autoimmune and anti-tumour T-cell responses by PTPN22

Abstract

A number of polymorphisms in immune-regulatory genes have been identified as risk factors for the development of autoimmune disease. PTPN22 (that encodes a tyrosine phosphatase) has been associated with the development of several autoimmune diseases, including type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus. PTPN22 regulates the activity and effector functions of multiple important immune cell types, including lymphocytes, granulocytes and myeloid cells. In this review, we describe the role of PTPN22 in regulating T-cell activation and effector responses. We discuss progress in our understanding of the impact of PTPN22 in autoimmune disease in humans and mouse models, as well as recent evidence suggesting that genetic manipulation of PTPN22 expression might enhance the efficacy of anti-tumour T-cell responses.

Keywords: T-cell; autoimmunity; signal transduction; tumour immunology.

Figure 1

CD8⁺ T‐cells lacking PTPN22 have sufficiently strong T‐cell receptor (TCR) signals to overcome transforming growth factor β (TGFβ)‐mediated suppression. (a) Control T‐cells stimulated through the TCR upregulate expression of transcription factors (TFs), activation markers such as CD25 and translocate NFAT into the nucleus within 24 hr. Subsequently, cells start to secrete IL‐2 and proliferate. (b) TGFβ added at the start of control cell culture inhibits TCR‐driven TFs, activation marker upregulation and NFAT translocation, resulting in lower levels of IL‐2 production, thereby less cell proliferation and more cell death by d3. (c) TCR stimulation is stronger in Ptpn22 ^−/− cells, resulting in more IL‐2 and more cell proliferation. (d) TGFβ is less able to suppress strong TCR signals, allowing Ptpn22 ^−/− cells to secrete enough IL‐2 to proliferate and survive by d3.