PTPN22 contributes to exhaustion of T lymphocytes during chronic viral infection

Abstract

The protein encoded by the autoimmune-associated protein tyrosine phosphatase nonreceptor type 22 gene, PTPN22, has wide-ranging effects in immune cells including suppression of T-cell receptor signaling and promoting efficient production of type I interferons (IFN-I) by myeloid cells. Here we show that mice deficient in PTPN22 resist chronic viral infection with lymphocytic choriomeningitis virus clone 13 (LCMV cl13). The numbers and function of viral-specific CD4 T lymphocytes is greatly enhanced, whereas expression of the IFNβ-induced IL-2 repressor, cAMP-responsive element modulator (CREM) is reduced. Reduction of CREM expression in wild-type CD4 T lymphocytes prevents the loss of IL-2 production by CD4 T lymphocytes during infection with LCMV cl13. These findings implicate the IFNβ/CREM/IL-2 axis in regulating T-lymphocyte function during chronic viral infection.

Extrinsic Protein Tyrosine Phosphatase Non-Receptor 22 Signals Contribute to CD8 T Cell Exhaustion and Promote Persistence of Chronic Lymphocytic Choriomeningitis Virus Infection

“…Similar to ours, Maine et al found that PTPN22-deficient mice show accelerated viral clearance of LCMV Cl13 infection by producing higher numbers of viral-specific CD4 and CD8 T lymphocytes with heightened function (30). PTPN22 deficiency did not result in a change in the number of GP 33–41 -specific LCMV-specific CTLs 8 dpi.…”

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

“…PTPN22 function in additional cell types likely has an important effect on T‐cell‐driven inflammation. For example, in myeloid cells, rather than act as a negative regulator, PTPN22 enhances production of type 1 interferons (IFNs) . Conversely, PTPN22 negatively regulates type 1 IFN‐receptor signalling pathways .…”

“…A clear example of cell‐extrinsic effects of PTPN22 on T‐cell function comes from studies of chronic viral infection. In this regard, several studies reported that PTPN22‐deficient mice were more efficient at clearing chronic lymphocytic choriomeningitis virus (LCMV) infection . Ptpn22 −/− mice infected with the persistent LCMV clone 13 had increased numbers and function of virus‐specific CD4 + T‐cells and CD8 + T‐cells .…”

“…In this regard, several studies reported that PTPN22‐deficient mice were more efficient at clearing chronic lymphocytic choriomeningitis virus (LCMV) infection . Ptpn22 −/− mice infected with the persistent LCMV clone 13 had increased numbers and function of virus‐specific CD4 + T‐cells and CD8 + T‐cells . However, cell transfer studies and mixed bone marrow chimera experiments indicated that the ability of Ptpn22 −/− T‐cells to resist exhaustion, and therefore clear virus load more efficiently, was not cell‐intrinsic .…”

“…Ptpn22 −/− mice infected with the persistent LCMV clone 13 had increased numbers and function of virus‐specific CD4 + T‐cells and CD8 + T‐cells . However, cell transfer studies and mixed bone marrow chimera experiments indicated that the ability of Ptpn22 −/− T‐cells to resist exhaustion, and therefore clear virus load more efficiently, was not cell‐intrinsic . Excessive production of type 1 IFN following infection can result in T‐cell exhaustion .…”