PTPN22 R620W Gene Editing in T Cells Enhances Low Avidity TCR Responses

Abstract

A genetic variant in the gene PTPN22 (R620W, rs2476601) is strongly associated with increased risk for multiple autoimmune diseases and has been linked to altered TCR regulation. Here, we utilize Crispr/Cas9 gene editing with donor DNA repair templates in human cord blood-derived, naive T cells to generate PTPN22 risk edited, non-risk edited (silent modification), or knock out T cells from the same donor. PTPN22 risk edited cells exhibited increased activation marker expression following non-specific TCR engagement, findings that mimicked PTPN22 KO cells. Next, using lentiviral delivery of T1D patient-derived islet-antigen specific TCRs, we demonstrate that loss of PTPN22 function led to enhanced signaling in T cells expressing a lower avidity self-reactive TCR. In this setting, loss of PTPN22 mediated enhanced proliferation and Th1 skewing. Importantly, expression of the risk variant in association with a lower avidity TCR also increased proliferation relative to PTPN22 non-risk T cells. Together, these findings suggest that, in primary human T cells, PTPN22 rs2476601 contributes to autoimmunity risk by permitting increased TCR signaling in mildly self-reactive T cells, thereby potentially expanding the self-reactive T cell pool and skewing this population toward an inflammatory phenotype.

Increased expression of protein tyrosine phosphatase nonreceptor type 22 alters early T‐cell receptor signaling and differentiation of CD4+ T cells in chronic heart failure

“…The non‐synonymous SNP in PTPN22 (rs2476601) was reported that contributing to influence the signal transduction of TCR in cohort of Type 1 Diabetes (T1D) 38 . And PTPN22 (R620W, rs2476601) increased the activation of TCR and mediated the transduction of the pro‐inflammation phenotype of CD4 + T cells in autoimmune diseases 39 . Genetic variants in PTPN22 may result in the changes of TCR signals and the generation of Tregs, which is worthy of further investigation.…”

“…38 And PTPN22 (R620W, rs2476601) increased the activation of TCR and mediated the transduction of the pro-inflammation phenotype of CD4 + T cells in autoimmune diseases. 39 Genetic variants in PTPN22 may result in the changes of TCR signals and the generation of Tregs, which is worthy of further investigation.…”

Causal relationship between rheumatoid arthritis and thyroid dysfunction: A two-sample Mendelian randomization study

“…Common allelic variations in CTLA-4 expression levels are major determinants of susceptibility to autoimmune diseases such as autoimmune thyroid disease and RA [32]. PTPN22 is associated with TCR signaling and participates in regulating CBL function in T cell receptor signaling pathways [35]. Mutations in this gene can alter TCR regulation and T cell activation, closely related to the increased risk of various autoimmune diseases, including RA and GD.…”

IKZF1 and UBR4 gene variants drive autoimmunity and Th2 polarization in IgG4-related disease

“…To examine whether these variants in the patients lower the threshold for T cell activation sufficiently to break tolerance of self-reactive T cells, we utilized an experimental system employing a low avidity, self-reactive TCR T1D2 isolated from a patient with type 1 diabetes mellitus (29)(30)(31). The T1D2 TCR recognizes a peptide derived from islet autoantigen islet-specific glucose-6 phosphatase catalytic subunit-related protein (IGRP) in the context of HLA-DRB1*04.…”