UVM Theses and Dissertations
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Author:
Lilley, Graham W. J.
Dept./Program:
Cell and Molecular Biology Program
Year:
2013
Degree:
M.S.
Abstract:
NKT cells are innate-like T cells that playa role in the pathogenesis of an array of infectious and autoimmune diseases. NKT cell number and function exhibit natural widespread variation in both humans and mice. Previously, we have shown that the Slam locus, located on the telomeric end of chromosome 1, contributes to this variation. However, neither the mechanism responsible for this control, nor the identification of specific gene(s) involved has been described. Here we show that the Slam locus regulates steady-state NKT cell homeostasis. Mixed bone-marrow chimeras of B6 (Slam-haplotype 1) and B6.129c1 (Slam-haplotype 2⁺) donor cells revealed that the Slam locus regulates steady-state liver NKT cell numbers.
Furthermore, we identify SLAMf6 as a critical modulator of NKT cell homeostasis and effector function. Cross-linking SLAMf6 on NKT cells enhanced apoptosis, in a caspase-3 independent manner, impaired proliferation and reduced IL-4 and IFNy production, with liver NKT cells exhibiting greater sensitivity to SLAMf6 cross-linking than spleen NKT cells. Examination of steady-state NKT cell homeostasis in Slamf6⁻/⁻ mice revealed an increase in BrdU incorporation by NKT cells. Finally, we demonstrate that the Slamf6.1 splice isoform, which is preferentially expressed on Slam-haplotype 2 strains, inhibits NKT cell function to a greater extent than the Slamf6.2 isoform. These data suggest that the role of SLAMf6 on NKT cells is inhibitory, and that Slamf6 contributes to the steady-state homeostasis of the peripheral NKT cell population. The finding that Slamf6.1 is more inhibitory than Slamf6.2 suggests that differential expression of these isoforms underlies the regulation of NKT cell number and function by the Slam locus.
Furthermore, we identify SLAMf6 as a critical modulator of NKT cell homeostasis and effector function. Cross-linking SLAMf6 on NKT cells enhanced apoptosis, in a caspase-3 independent manner, impaired proliferation and reduced IL-4 and IFNy production, with liver NKT cells exhibiting greater sensitivity to SLAMf6 cross-linking than spleen NKT cells. Examination of steady-state NKT cell homeostasis in Slamf6⁻/⁻ mice revealed an increase in BrdU incorporation by NKT cells. Finally, we demonstrate that the Slamf6.1 splice isoform, which is preferentially expressed on Slam-haplotype 2 strains, inhibits NKT cell function to a greater extent than the Slamf6.2 isoform. These data suggest that the role of SLAMf6 on NKT cells is inhibitory, and that Slamf6 contributes to the steady-state homeostasis of the peripheral NKT cell population. The finding that Slamf6.1 is more inhibitory than Slamf6.2 suggests that differential expression of these isoforms underlies the regulation of NKT cell number and function by the Slam locus.