PTPN22 encodes a tyrosine phosphatase that inhibits Src-family kinases responsible for antigen receptor signaling in lymphocytes, and is strongly linked with susceptibility to a number of autoimmune diseases. As strength of TCR signal is critical to the thymic selection of regulatory T cells (Tregs) we examined the effect of murine PTPN22 deficiency on Treg development and function. In the thymus, numbers of pre-Tregs and Tregs increased inversely with the level of PTPN22. This increase in Tregs persisted in the periphery and could play a key part in the reduced severity observed in the PTPN22 deficient mice of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. This could explain the lack of association of certain autoimmune conditions with PTPN22 risk alleles.
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.
Weak T-cell antigen receptor (TCR)-ligand interactions are sufficient to activate naïve CD8+ T cells, but generally do not result in tumor eradication. How differences in TCR affinity affect the regulation of T-cell function in an immunosuppressive tumor environment has not been investigated. We have examined the functional differences of high- vs. low-affinity CD8+ T cells and we observed that infiltration, accumulation, survival and cytotoxicity within the tumor are severely impacted by the strength of TCR-ligand interactions. In addition, high-affinity CD8+ T cells were found to exhibit lower expression of inhibitory molecules including PD-1, LAG-3 and NKG2A, thus being less susceptible to suppressive mechanisms. Interferon γ and autocrine interleukin-2 were both found to influence the level of expression of these molecules. Interestingly, although high-affinity CD8+ T cells were superior to low-affinity CD8+ T cells in their ability to effect tumor eradication, they could be further improved by the presence of tumor specific CD4+ T cells. These findings illustrate the importance of both TCR affinity and tumor-specific CD4 help in tumor immunotherapy.
Nonobese diabetic (NOD) mice congenic for C57BL/10 (B10)-derived genes in the Idd9 region of chromosome 4 are highly protected from type 1 diabetes (T1D). Idd9 has been divided into three protective subregions (Idd9.1, 9.2, and 9.3), each of which partially prevents disease. In this study we have fine-mapped the Idd9.1 and Idd9.2 regions, revealing further genetic complexity with at least two additional subregions contributing to protection from T1D. Using the NOD sequence from bacterial artificial chromosome clones of the Idd9.1 and Idd9.2 regions as well as whole-genome sequence data recently made available, sequence polymorphisms within the regions highlight a high degree of polymorphism between the NOD and B10 strains in the Idd9 regions. Among numerous candidate genes are several with immunological importance. The Idd9.1 region has been separated into Idd9.1 and Idd9.4, with Lck remaining a candidate gene within Idd9.1. One of the Idd9.2 regions contains the candidate genes Masp2 (encoding mannan-binding lectin serine peptidase 2) and Mtor (encoding mammalian target of rapamycin). From mRNA expression analyses, we have also identified several other differentially expressed candidate genes within the Idd9.1 and Idd9.2 regions. These findings highlight that multiple, relatively small genetic effects combine and interact to produce significant changes in immune tolerance and diabetes onset.Electronic supplementary materialThe online version of this article (doi:10.1007/s00335-013-9466-y) contains supplementary material, which is available to authorized users.
In the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D), insulin-dependent diabetes (Idd) loci control the development of insulitis and diabetes. Independently, protective alleles of Idd3/Il2 or Idd5 are able to partially protect congenic NOD mice from insulitis and diabetes, and to partially tolerize islet-specific CD8+ T cells. However, when the two regions are combined, mice are almost completely protected, strongly suggesting the existence of genetic interactions between the two loci. Idd5 contains at least three protective sub-regions/causative gene candidates, Idd5.1/Ctla4, Idd5.2/Slc11a1 and Idd5.3/Acadl, yet it is unknown which of them interacts with Idd3/Il2. Through the use of a series of novel congenic strains containing the Idd3/Il2 region and different combinations of Idd5 sub-region(s), we defined these genetic interactions. The combination of Idd3/Il2 and Idd5.3/Acadl was able to provide nearly complete protection from T1D, but all three Idd5 sub-regions were required to protect from insulitis and fully restore self-tolerance. By backcrossing a Slc11a1 KO allele onto the NOD genetic background, we have demonstrated that Slc11a1 is responsible for the diabetes protection resulting from Idd5.2. We also used Slc11a1 KO-SCID and Idd5.2-SCID mice to show that both loss-of-function alleles provide protection from insulitis when expressed on the SCID host alone. These results lend further support to the hypothesis that Slc11a1 is Idd5.2.
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