The effect of the autoimmunity-associated gene, PTPN22, on a BXSB-derived model of lupus

Abstract

A single nucleotide polymorphism in PTPN22 is linked to increased disease susceptibility in a range of autoimmune diseases including systemic lupus erythematosus (SLE). PTPN22 encodes the Lyp phosphatase that dampens TCR signaling and is necessary for signaling downstream of toll-like receptors in myeloid cells. To understand these dual functions in disease, we examined the impact of deficiency in PTPN22 on a spontaneous murine model of SLE. Male PTPN22 KO mice carrying BXSB chromosome 1 and the Yaa disease accelerating factor, developed disease at a similar rate and severity as PTPN22 WT. In contrast, although female BXSB mice showed no differences in survival in the absence of PTPN22, autoantibody production was significantly increased and splenic populations associated with pathogenesis in this model were expanded in the PTPN22 KO group. These findings support the notion that when coupled with other predisposing autoimmunity genes, PTPN22 deficiency contributes to a predisposition to lupus pathogenesis.

PTPN22 contributes to exhaustion of T lymphocytes during chronic viral infection

“…The absence of PTPN22 or the expression of the R620W mutant human form of PTPN22 results in reduced IFN-I production by myeloid cells. We recently have confirmed these findings in plasmacytoid dendritic cells (pDCs) stimulated with TLR7 (Toll-like receptor 7) ligands (35). Based on the reported functions of PTPN22 in T cells and innate immune cells, we hypothesized that deficiency in PTPN22 would result in improved clearance of chronic viral infection because of enhanced T-cell responses and reduced IFN-I production.…”

“…PTPN22 −/− and WT mice were infected with LCMV cl13, and spleens were collected and analyzed on day 14. Similar numbers of GP [33][34][35][36][37][38][39][40][41] tetramer-positive CD8 T cells were found in the spleens of PTPN22 −/− and WT mice (Fig. 7A).…”

“…7C). Although the percentage of GP [33][34][35][36][37][38][39][40][41] tetramer-positive cells that can produce TNFα or IL-2 is very low in WT mice, a significantly higher percentage of GP 33-41 tetramer-positive CD8 T cells from PTPN22 −/− mice produce both cytokines (Fig. 7 D-F).…”

“…To assess the function of the CD8 T cells, splenocytes were restimulated with GP 33-41 peptide, and intracellular staining for cytokines was performed on GP 33-41 tetramer-positive cells. The GP [33][34][35][36][37][38][39][40][41] tetramer-positive cells from PTPN22 −/− mice showed broader polyfunctionality than the cells from WT mice, with a larger pool of triple-and double-cytokinepositive cells (Fig. 7C).…”

“…Intracellular Cytokine Staining. Splenocyte populations were plated at 2 × 10 5 cells per well in a 96-well plate and were stimulated with LCMV peptides (GP 61-80 and GP [33][34][35][36][37][38][39][40][41] ) for 4 h in the presence of Brefeldin A (Sigma Aldrich). For pDC intracellular cytokine staining, splenocytes were cultured as above in the presence of Brefeldin A for 3 h. Cells were stained for surface markers and then were fixed in Cytofix/Cytoperm buffer (BD Bioscience).…”