Influence of a Non-NK Complex Region of Chromosome 6 on CD4+ Invariant NK T Cell Homeostasis

Abstract

The number and function of immunoregulatory invariant NKT (iNKT) cells are genetically controlled. A defect of iNKT cell ontogeny and function has been implicated as one causal factor of NOD mouse susceptibility to type 1 diabetes. Other factors of diabetes susceptibility, such as a decrease of regulatory T cell function or an increase in TLR1 expression, are corrected in diabetes-resistant Idd6 NOD.C3H 6.VIII congenic mice. Thus, we surmised that the iNKT cell defects found in NOD mice may also be rescued in congenic mice. Unexpectedly, we found, in both the thymus and the periphery, a 50% reduction in iNKT cell number in NOD.C3H 6.VIII mice as compared with NOD mice. This reduction only affected CD4+ iNKT cells, and left the double negative iNKT cells unchanged. In parallel, the production of IL-4 and IFN-γ following α-GalCer stimulation was proportionally reduced. Using three subcongenic strains, we have narrowed down the region controlling iNKT development within Idd6 (5.8 Mb) to Idd6.2 region (2.5 Mb). Idd6 region had no effect on NK cell number and in vivo cytotoxic activity. These results indicate that the role of iNKT cells in diabetes development is equivocal and more complex than initially considered. In addition, they bring strong evidence that the regulation of CD4+ iNKT cell production is independent from that of DN iNKT cells, and involves genes of the Idd6 locus.

Natural Killer T Cells and Autoimmune Disease

“…These defects in NKT cell development were already observed before birth and developed after the CD4 + CD8 + double-positive stage of thymic T cell development [56]. Genetic control of thymic NKT cell numbers has been mapped to multiple genetic loci, including Nkt1 on distal chromosome 1, Nkt2 on chromosome 2, and Idd6 on chromosome 6 [57][58][59][60][61]. The Nkt1 locus includes the signaling lymphocyte activation molecule (SLAM) gene cluster, which associates with the SLAM-associated adaptor protein (SAP), a pathway that has been implicated in NKT cell development and function [19,[62][63][64][65].…”

Linking the Circadian Rhythm Gene Arntl2 to Interleukin 21 Expression in Type 1 Diabetes

“…The Idd6 candidate region (2), showing resistance to the spontaneous development of diabetes, overlaps with the candidate region for the resistance of immature T cells to dexamethasone (3-5) and for the control of low rates of proliferation in immature NOD thymocytes (6). Idd6 controls the activity of regulatory CD4 + T cells and invariant natural killer T cells (7,8).Previous research has also focused on the identification of candidate genes and the underlying molecular networks (9-13). The analysis of three NOD.C3H subcongenic strains (6.VIIIa, 6.VIIIb, and 6.VIIIc) derived from the original 6.VIII congenic strain showed the presence of at least three diabetes-related subloci contributing to the overall T1D resistance (Idd6.1, Idd6.2, Idd6.3), but Idd6.3 alone controls the suppressive activity of splenocytes (10).…”

“…The Idd6 candidate region (2), showing resistance to the spontaneous development of diabetes, overlaps with the candidate region for the resistance of immature T cells to dexamethasone (3)(4)(5) and for the control of low rates of proliferation in immature NOD thymocytes (6). Idd6 controls the activity of regulatory CD4 + T cells and invariant natural killer T cells (7,8).…”