ABSTRACT
Several immune regulatory cell types participate in the protection against autoimmune diseases such as autoimmune diabetes. Of these immunoregulatory cells, we and others have shown that peripheral CD4-CD8- double negative (DN) T cells can induce antigen-specific immune tolerance. Particularly, we have described that diabetes-prone mice exhibit a lower number of peripheral DN T cells compared to diabetes-resistant mice. Identifying the molecular pathways that influence the size of the DN T cell pool in peripheral lymphoid organs may thus be of interest for maintaining antigen-specific immune tolerance. Hence, through immunogenetic approaches, we found that two genetic loci linked to autoimmune diabetes susceptibility, namely Idd2 and Idd13, independently contribute to the partial restoration of DN T cell proportion in secondary lymphoid organs. We now extend these findings to show an interaction between the Idd2 and Idd13 loci in determining the number of DN T cells in secondary lymphoid organs. Using bioinformatics tools, we link potential biological pathways arising from interactions of genes encoded within the two loci. By focusing on cell cycle, we validate that both the Idd2 and Idd13 loci influence RAD51 expression as well as DN T cell progression through the cell cycle. Altogether, we find that genetic interactions between Idd2 and Idd13 loci modulate cell cycle progression, which contributes, at least in part, to defining the proportion of DN T cells in secondary lymphoid organs.
Subject(s)
Diabetes Mellitus/immunology , Immune Tolerance/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Antigens, Differentiation, T-Lymphocyte/genetics , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Diabetes Mellitus/genetics , Epistasis, Genetic , Genetic Predisposition to Disease/genetics , Insulins/metabolism , Mice , Mice, Transgenic , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/metabolismABSTRACT
Assessing the genetic variation and distribution of immune genes across heterogeneous environmental conditions in wild species is essential to further our understanding of the role of pathogen pressure and potential resistance or prevalence in hosts. Researchers have recently investigated ß-defensin genes in the wild, because their variability suggests that they may play an important role in innate host defense. This study investigated the variation occurring at 6 innate immune genes of the ß-defensin family in a declining population of tree swallows (Tachycineta bicolor) in southern Québec, Canada (N = 160). We found that all 6 genes showed synonymous and nonsynonymous single nucleotide polymorphisms (SNPs) within the exon coding for the mature peptide. These results indicated that this group of genes was diverse in tree swallows. Our results suggested a potential interaction of this group of genes with fluctuating pathogen diversity, however, we found no sign of positive or negative selection. We assessed whether or not the distribution of genetic diversity of ß-defensin genes in our study population differed between 2 regions that strongly differ in their level of agricultural intensification. Adults are highly philopatric to their breeding sites and their immunological responses differ between these 2 regions. However, we found little evidence that the level and distribution of genetic variability differed between these heterogeneous environmental conditions. Further studies should aim to assess the link between genetic diversity of ß-defensin genes and fitness-related traits in wild populations.
