Influence of a non-NK complex region of chromosome 6 on CD4+ invariant NK T cell homeostasis.
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-gamma following alpha-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.
Vallois
David
D
Institut National de la Santé et de la Recherche Médicale U561, Université Paris Descartes, Saint Vincent de Paul Hospital, Paris, France.
Gagnerault
Marie-Claude
MC
Avner
Philip
P
Rogner
Ute C
UC
Boitard
Christian
C
Benlagha
Kamel
K
Herbelin
André
A
Lepault
Françoise
F
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D033481:Chromosomes, Mammalian / Q000235:genetics* / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D006706:Homeostasis / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology
D016693:Receptors, Antigen, T-Cell, alpha-beta; D015847:Interleukin-4; D007371:Interferon-gamma