Session Type: Abstract Submissions (ACR)
Background/Purpose: Previous studies from our lab have shown that the introgression of a NZB chromosome 1 (c1) interval extending from 135 to179 Mb onto the non-autoimmune C57BL/6 (B6) background results in increased B and T cell activation, elevated anti-nuclear antibodies (ANA), and fatal kidney disease. Similar introgression of a NZB c4 interval with mapped susceptibility loci extending from 30 to 150Mb onto the B6 background resulted in the expansion of splenic invariant Natural Killer T (iNKT) and CD5+ B cells in the absence of autoimmunity. To define the role of NZB c4 in autoimmunity, bicongenic (c1c4) mice were produced with both NZB c4 and c1 intervals. Despite the presence of c1 autoimmune augmenting genes, c1c4 mice had reduced renal disease, increased survival, and a shift towards less pathogenic IgG1 autoantibodies. Interestingly, bicongenic mice had retained an expansion of splenic iNKT cells. Recent studies have shown that activated iNKT cells can rapidly secrete large quantities of Th1 or Th2 cytokines, thereby altering the progression and initiation of autoimmunity. In this study we sought to define the role of iNKT cells in the suppression of spontaneous autoimmunity.
Methods: NKT cells were stimulated in vivo by intravenous injection with 2µg of α-GalCer. Cellular phenotypes were examined by flow cytometry of de novo splenocytes. Intracellular production of IFNγ, IL-17, and IL-4 was measured by flow cytometry following 4 to 5 hour stimulation with PMA and Ionomycin.
Results: The functional capacity of NKT cells was examined by in vivo stimulation with α-GalCer. Following activation, there was a significant decrease in the frequency of IFNγ and IL-4 producing splenic iNKT cells in c1 and c1c4 mice when compared to B6 and c4 controls. However, the expansion of splenic iNKT cells normalized the total number of IFNγ and IL-4 producing iNKT cells in c1c4 mice to B6 levels. In order to more conclusively define the role of iNKT cells in initiation and progression of spontaneous autoimmunity, CD1d knockout mice were bred onto the suppressed bicongenic background. Characterization of aged CD1d knockout bicongenic mice, that lack NKT cells, revealed an increase in germinal center B cells, memory/effector T cells, and IL-17 or IFNγ producing T cells when compared to bicongenic mice. The CD1d knockout had no impact on the number of IL-10 producing CD5+B cells.
Conclusion: These data suggest that suppressed bicongenic mice have a normalization of iNKT cell cytokine production through a numeric expansion. Furthermore, knockout of NKT cells on the suppressed background resulted in an increase in cellular activation suggesting a protective role for iNKT cells in the pathogenesis of spontaneous autoimmunity.
N. H. Chang,
J. E. Wither,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-numeric-expansion-of-invariant-natural-killer-t-cells-protects-against-the-progression-of-fatal-autoimmunity-in-lupus-prone-mice/