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Immunogenetics. 2018 Aug;70(8):495-509. doi: 10.1007/s00251-018-1060-8. Epub 2018 Apr 25.

Genetic interaction between two insulin-dependent diabetes susceptibility loci, Idd2 and Idd13, in determining immunoregulatory DN T cell proportion.

Author information

1
Division of Immunology-oncology, Maisonneuve-Rosemont Hospital, Research Center, Montréal, 5415 l'Assomption Blvd, Québec, H1T 2M4, Canada.
2
Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, Québec, H3C 3J7, Canada.
3
Division of Experimental Medicine, McGill University, Montréal, Québec, H4A 3J1, Canada.
4
Lady Davis Institute, Jewish General Hospital, 3755 Côte Ste-Catherine, Montréal, Québec, H3T 1E2, Canada.
5
Division of Experimental Medicine, McGill University, Montréal, Québec, H4A 3J1, Canada. alexandre.orthwein@mcgill.ca.
6
Lady Davis Institute, Jewish General Hospital, 3755 Côte Ste-Catherine, Montréal, Québec, H3T 1E2, Canada. alexandre.orthwein@mcgill.ca.
7
Department of Oncology, McGill University, Montréal, Québec, H4A 3J1, Canada. alexandre.orthwein@mcgill.ca.
8
Division of Immunology-oncology, Maisonneuve-Rosemont Hospital, Research Center, Montréal, 5415 l'Assomption Blvd, Québec, H1T 2M4, Canada. sylvie.lesage@umontreal.ca.
9
Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, Québec, H3C 3J7, Canada. sylvie.lesage@umontreal.ca.

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.

KEYWORDS:

Cell cycle; Double negative T cells; Transgenic mice; Type 1 diabetes

PMID:
29696366
DOI:
10.1007/s00251-018-1060-8
[Indexed for MEDLINE]

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