Abstract
Invariant natural killer T (iNKT) cells are innate-like T lymphocytes. They quickly respond to antigenic stimulation by producing copious amounts of cytokines and chemokines. iNKT precursors differentiate into three subsets iNKT1, iNKT2, and iNKT17 with specific cytokine production signatures. While key transcription factors drive subset differentiation, factors that regulate iNKT subset homeostasis remain incompletely defined. Transcriptomic analyses of thymic iNKT subsets indicate that Serpinb1a is one of the most specific transcripts for iNKT17 cells suggesting that iNKT cell maintenance and function may be regulated by Serpinb1a. Serpinb1a is a major survival factor in neutrophils and prevents cell death in a cell-autonomous manner. It also controls inflammation in models of bacterial and viral infection as well as in LPS-driven inflammation. Here, we examined the iNKT subsets in neutropenic Serpinb1a −/− mice as well as in Serpinb1a −/− mice with normal neutrophil counts due to transgenic re-expression of SERPINB1 in neutrophils. In steady state, we found no significant effect of Serpinb1a-deficiency on the proliferation and numbers of iNKT subsets in thymus, lymph nodes, lung, liver and spleen. Following systemic activation with α-galactosylceramide, the prototypic glycolipid agonist of iNKT cells, we observed similar serum levels of IFN-γ and IL-4 between genotypes. Moreover, splenic dendritic cells showed normal upregulation of maturation markers following iNKT cell activation with α-galactosylceramide. Finally, lung instillation of α-galactosylceramide induced a similar recruitment of neutrophils and production of iNKT-derived cytokines IL-17, IFN-γ, and IL-4 in wild-type and Serpinb1a −/− mice. Taken together, our results indicate that Serpinb1a, while dominantly expressed in iNKT17 cells, is not essential for iNKT cell homeostasis, subset differentiation and cytokine release.
Highlights
Invariant natural killer T cells are tissue resident innatelike T lymphocytes that respond to lipid antigens
The latter are constitutively deficient in endogenous mouse Serpinb1a and express human SERPINB1 in neutrophils, which rescues the neutropenic phenotype of Sb1a−/− mice (Figure 1A), as described previously [27]
We found that the percentages of iNKT17 cells defined as CD4negCD122neg were increased in thymus of Sb1a−/− mice
Summary
Invariant natural killer T (iNKT) cells are tissue resident innatelike T lymphocytes that respond to lipid antigens. The TCR of iNKT cells is specific for exogenous and endogenous lipid antigens presented by CD1d, a non-polymorphic MHC class I-like molecule. This specificity is mediated by their semi-invariant TCR composed of an invariant TCRa chain (Va14-Ja18 in mice, Va24-Ja18 in humans) paired with a limited set of TCRb chains (Vb2, Vb7, or Vb8 in mice, Vb11 in humans) [2]. The majority of iNKT cells proceed to the double positive stage (DP, CD4+CD8+) and they are selected following strong interactions with other DP thymocytes expressing CD1d in the thymus medulla [5,6,7]. One subset of iNKT cells differentiates already at the double negative (DN) stage and remains CD4neg [8]
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