Loss-of-function of PTPN2 promotes pathogenic loss of FoxP3+ in RORgt+ Tregs [RNA-seq]

Genetic variants at the PTPN2 locus, which encodes the tyrosine phosphatase PTPN2, cause reduced gene expression and are linked to rheumatoid arthritis (RA) and other autoimmune diseases. PTPN2 inhibits signaling through the T cell and cytokine receptors and loss of PTPN2 promotes T cell expansion and CD4 and CD8-driven autoimmunity. However, it remains unknown whether loss of PTPN2 in FoxP3+ regulatory T cells (Treg) plays a role in autoimmunity. Here we show that a reduction in Ptpn2 expression, comparable to that reported in human carriers of autoimmune-predisposing PTPN2 variants, unexpectedly enhances the severity of autoimmune arthritis through a Treg-intrinsic mechanism. Mechanistically, we found that through dephosphorylation of STAT3, Ptpn2 inhibits IL-6-driven pathogenic loss of FoxP3 after Tregs have acquired RORgt expression, at a stage when chromatin accessibility for STAT3-targeted IL-17 associated transcription factors is maximized. We conclude that PTPN2 promotes FoxP3 stability in RORgt+ Treg and that loss of function of PTPN2 in Treg contributes to the association between PTPN2 and autoimmunity. Overall design: Gene expression analysis by RNA-Sequencing of Tregs and exTregs isolated during arthritis development in mice or after in vitro culutre.

编码酪氨酸磷酸酶PTPN2的PTPN2基因座上的遗传变异，可导致该基因表达下调，并与类风湿关节炎（RA）及其他自身免疫疾病密切相关。PTPN2能够抑制T细胞与细胞因子受体介导的信号转导，而PTPN2功能缺失会促进T细胞扩增，以及CD4⁺和CD8⁺ T细胞驱动的自身免疫反应。然而，目前仍不清楚FoxP3⁺调节性T细胞（Treg）中PTPN2的缺失是否参与自身免疫的发生发展。本研究结果显示，与自身免疫易感PTPN2变异携带者中观测到的PTPN2表达降低程度相当的Ptpn2表达下调，竟通过Treg固有机制意外加重了自身免疫性关节炎的严重程度。
机制层面研究表明，在Treg获得RORγt表达后，Ptpn2可通过对STAT3的去磷酸化作用，抑制IL-6介导的FoxP3病理性丢失；此时STAT3靶向的IL-17相关转录因子的染色质开放程度达到峰值。
本研究最终证实：PTPN2可维持RORγt⁺ Treg中的FoxP3稳定性，而Treg中PTPN2的功能缺失，是PTPN2与自身免疫疾病相关联的潜在机制之一。
整体实验设计：通过RNA测序对小鼠关节炎造模过程中或体外培养分离得到的Treg及exTregs进行基因表达分析。