T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice

Abstract

Many autoimmune diseases exhibit familial aggregation, indicating that they have genetic determinants. Single nucleotide polymorphisms in PTPN2, which encodes T cell protein tyrosine phosphatase (TCPTP), have been linked with the development of several autoimmune diseases, including type 1 diabetes and Crohn's disease. In this study, we have identified TCPTP as a key negative regulator of TCR signaling, which might explain the association of PTPN2 SNPs with autoimmune disease. We found that TCPTP dephosphorylates and inactivates Src family kinases to regulate T cell responses. Using T cell-specific TCPTP-deficient mice, we established that TCPTP attenuates T cell activation and proliferation in vitro and blunts antigen-induced responses in vivo. TCPTP deficiency lowered the in vivo threshold for TCR-dependent CD8 + T cell proliferation. Consistent with this, T cell-specific TCPTP-deficient mice developed widespread inflammation and autoimmunity that was transferable to wild-type recipient mice by CD8 + T cells alone. This autoimmunity was associated with increased serum levels of proinflammatory cytokines and anti-nuclear antibodies, T cell infiltrates in non-lymphoid tissues, and liver disease. These data indicate that TCPTP is a critical negative regulator of TCR signaling that sets the threshold for TCR-induced naive T cell responses to prevent autoimmune and inflammatory disorders arising.

PTPN2 attenuates T-cell lymphopenia-induced proliferation

“…1c). The increase in PTPN2 protein levels in SP thymocytes and naive T cells versus DP thymocytes is consistent with a role in thymic selection 23,26 and the attenuation of T-cell responses to self in the periphery.…”

“…3a). Previously, we have reported that Lck-Cre;Ptpn2 fl/fl mice develop an effector/memory phenotype as early as 4 weeks of age that progressively develops over time 23 . The Lck-Cre;Ptpn2 fl/fl T cells arising from fast-paced LIP were phenotypically similar to those in 6-week old LckCre;Ptpn2 fl/fl mice, wherein a proportion of the antigenexperienced activated T cells (CD49d hi CD44 hi CD62L lo ) were also IL7Ra lo KLRG1 hi ( Supplementary Fig.…”

“…On the other hand CD8 þ memory T-cell (CD62L hi CD44 hi ) LIP is independent of contact with selfpeptide-MHC and reliant on gc chain cytokines, especially IL-15 (refs 1,35,36). Since JAK1/3 and STAT5 can serve as PTPN2 substrates 37,38 , PTPN2 has the potential to regulate T-cell LIP, not only through the attenuation of TCR-SFK signalling 23,24 , but also through the attenuation of cytokine signalling. To assess the impact of PTPN2 deficiency on cytokine-induced CD8 þ T-cell LIP, we first assessed responses in CD8 þ (CD62L hi CD44 hi ) memory T cells.…”

“…At least one of the PTPN2 SNPs implicated in type 1 diabetes has been associated with a B40% decrease in PTPN2 expression in T cells 22 . Recent studies have identified PTPN2 (also known as T-cell PTP; TCPTP) as a key regulator of TCR signalling in CD4 þ and CD8 þ T cells, serving to dephosphorylate and inactivate the Src family protein tyrosine kinases (SFK) Lck and Fyn that are instrumental in instigating TCR signalling 23,24 . PTPN2 has also previously been implicated in the dephosphorylation of Janus-activated kinases (JAK)-1/3 and several signal transducer and activator of transcription (STAT) family members for the attenuation of cytokine signalling 25 .…”

“…PTPN2 has also previously been implicated in the dephosphorylation of Janus-activated kinases (JAK)-1/3 and several signal transducer and activator of transcription (STAT) family members for the attenuation of cytokine signalling 25 . T cell-specific PTPN2 deficiency enhances CD4 þ and CD8 þ T-cell responses in vivo and lowers the threshold for TCR-instigated responses so that CD8 þ T cells respond more efficiently to peptide antigens with suboptimal TCR affinity 23,24 . Moreover, T cell-specific PTPN2-deficient mice (Lck-Cre;Ptpn2 fl/fl ) develop widespread inflammation and spontaneous autoimmunity with age 23,24 , but the basis for this remains unclear.…”