PTPN22 Controls the Germinal Center by Influencing the Numbers and Activity of T Follicular Helper Cells

Abstract

A single nucleotide polymorphism in the protein tyrosine phosphatase nonreceptor type 22 gene (PTPN22), that encodes the Lyp tyrosine phosphatase LypR620W, has been linked to a number of autoimmune diseases including type I diabetes, rheumatoid arthritis and systemic lupus erythematosus. Studies in PTPN22 KO mice and in mice expressing the mouse homolog of the pro-autoimmune allele, PepR619W, have reported increased germinal center activity and enhanced antibody production. Here we present findings that explain the basis for increased germinal center activity in PTPN22 mutant mice. As compared with their wild type equivalents, TFH cells from PTPN22 KO mice proliferate and accumulate to a greater extent, and exhibit enhanced production of IL-21. The follicular regulatory T cells (TFR) in PTPN22 KO mice do not expand to effectively regulate these TFH cells, resulting in an increase in B cell numbers and antibody production. This is evident in the KBxN mouse model of arthritis in which PTPN22 deficiency results in increased severity of disease. Our findings demonstrate the importance of cell type specific PTPN22 activity on regulation of antibody production.

A Functional Polymorphism of Ptpn22 Is Associated with Type 1 Diabetes in the BioBreeding Rat

“…3B-D). This is consistent with the findings of Maine et al, which demonstrated that, within the germinal centers, the loss of Ptpn22 primarily affected the survival, proliferation, and cytokine secretion of T follicular helper cells and had little effect on B cell function (15). However, it is of note that the analyses performed on the Iddm26.2 congenic sublines did not specifically discriminate between naive and memory B cells, and may thus have prevented the observation of more subtle, subset-specific phenotypes.…”

“…Although recent evidence has demonstrated that Ptpn22 controls germinal center and Ab responses by modulating the activity of T follicular helper cells (15), several studies also suggest a direct role of Ptpn22 in B cell function (16,17). In addition to its role in cells of the lymphoid lineage, Ptpn22 has also been shown to facilitate type I IFN responses in myeloid cells after TLR engagement, further establishing its diverse and important role in the regulation of the immune system (18).…”

CD4 T cell differentiation in type 1 diabetes

“…Several studies have implicated persistent antigen presentation in Tfh differentiation [117,143], a notion that might fit with the inability of self-antigens to be cleared in autoimmune settings. Interestingly, Tfh differentiation is subject to regulation by a number of pathways that are linked genetically to autoimmunity, including the CD28/cytotoxic T lymphocyte antigen (CTLA)-4 axis [144][145][146][147][148][149][150], IL-2 [127][128][129][130] and the lymphoid-specific tyrosine phosphatase (LYP) encoded by protein tyrosine phosphatase, non-receptor type 22 (PTPN22) [151]. The link between these loci and disease initiation is complex, but modulation of Tfh differentiation adds an additional consideration to the other known roles of the candidate genes in these locations.…”

PTPN22 contributes to exhaustion of T lymphocytes during chronic viral infection

“…Genome-wide association studies demonstrated the association of a minor allele of PTPN22 (R620W) with a number of autoimmune diseases including type I diabetes, rheumatoid arthritis, and systemic lupus erythematosus, among others (24)(25)(26). PTPN22-deficient mice have been instrumental in uncovering the role of this gene in T-cell function (27)(28)(29)(30)(31)(32). Aged mice develop splenomegaly and enlarged lymph nodes that exhibit the accumulation of effector/memory T cells, enlarged spontaneous germinal centers, and increased (non-autoreactive) serum IgG.…”