Role of SLAM in NKT Cell Development Revealed by Transgenic Complementation in NOD Mice

Abstract

Allelic variation of SLAM expression on CD4+CD8+ thymocytes has been proposed to play a major role in NKT cell development. In this article, this hypothesis is tested by the production of subcongenic mouse strains and Slamf1 transgenic lines. The long isoform of the C57BL/6 allele of Slamf1 was transgenically expressed on CD4+CD8+ thymocytes under control of an hCD2 minigene. NOD.Nkrp1b.Tg(Slamf1)1 mice, which had a 2-fold increase in SLAM protein expression on CD4+CD8+ thymocytes, had a 2-fold increase in numbers of thymic NKT cells. The additional thymic NKT cells in NOD.Nkrp1b.Tg(Slamf1)1 mice were relatively immature, with a similar subset distribution to those of congenic NOD.Nkrp1b.Nkt1 and NOD.Nkrp1b.Slamf1 mice, which also express increased levels of SLAM on CD4+CD8+ thymocytes and produce larger numbers of NKT cells. Transgenic enhancement of SLAM expression also increased IL-4 and IL-17 production in response to TCR-mediated stimulation. Paradoxically, NOD.Nkrp1b.Tg(Slamf1)2 mice, which had a 7-fold increase in SLAM expression, showed no significant increase in NKT cells numbers; on the contrary, at high transgene copy number, SLAM expression levels correlated inversely with NKT cell numbers, consistent with a contribution to negative selection. These data confirm a role for SLAM in controlling NKT cell development and are consistent with a role in both positive and negative thymic selection of NKT cells.

Genetic control of murine invariant natural killer T cells maps to multiple type 1 diabetes regions

“…Compared to the previous linkage studies, the splenic QTL on Chr 1 (peaks at 172.96Mb) identified here overlaps with the Nkt1 locus that contains Slamf1 and Slamf6 genes known to regulate iNKT-cell development 27, 29 . However, we did not detect a QTL overlapping the Nkt2 region on Chr 2 or the Idd9.1 region on Chr 4 reported to control iNKT-cell development.…”

“…Nkrp1 b mice identified two loci respectively on Chromosomes (Chr) 1 and 2 significantly linked to the frequency of thymic iNKT-cells 26 . Both loci ( Nkt1 and Nkt2 ) were subsequently confirmed by congenic analysis, and Slamf1 and Slamf6 within the Nkt1 locus have also been shown to regulate iNKT-cell development 23, 27–29 . The B6-derived Nkt2 locus has also been shown to suppress T1D in NOD mice 23 .…”

Genetic control of murine invariant natural killer T-cell development dynamically differs dependent on the examined tissue type

“…Nkrp1 b mice identified two loci respectively on Chr 1 and 2 significantly linked to the frequency of thymic iNKT-cells 43 . Both loci ( Nkt1 and Nkt2 ) were subsequently confirmed by congenic analysis, and Slamf1 and Slamf6 within the Nkt1 locus have also been shown to regulate iNKT-cell development 17, 44-46 . To our surprise, neither locus was detected by our genome-wide association mapping across strains for thymic iNKT-cell frequencies.…”

SLAM‐associated protein favors the development of iNKT2 over iNKT17 cells

“…Last, iNKT cells are implicated in autoimmune pathologies, namely type 1 diabetes . It is noteworthy that NOD mice, the spontaneous models of autoimmune diabetes, show reduced SLAM expression together with decreased total iNKT cell counts . On the other hand, NOD mice exhibit a higher frequency and absolute number of iNKT17 cells capable to enhance the incidence of diabetes .…”