Increased cytotoxicity of CD4+ invariant NKT cells against CD4+CD25hiCD127lo/- regulatory T cells in allergic asthma

CD4(+)CD25(hi)CD127(lo/-) regulatory T cells (Treg) have been implicated in the resolution of asthma-associated inflammation while the opposite role of CD4(+) invariant NKT (iNKT) cells has been the subject of recent investigations. Studies here focused on mechanisms of interaction between CD4(+) iNKT cells and Treg to further explore their roles in allergic asthma (AA). Flow cytometry analysis revealed a significant increase in the expression of the natural cytotoxicity receptors NKp30 and NKp46 by CD4(+) iNKT cells in AA subjects compared to healthy controls (HC) and non-allergic asthmatics (NA). Subsequent intracellular staining showed that CD4(+) iNKT cells also expressed higher levels of granzyme B and perforin in AA than HC. In in vitro killing assays, AA CD4(+) iNKT cells selectively killed autologous Treg, but not CD4(+)CD25(-) T cells, more potently than HC and NA counterparts. This increased cytotoxicity positively correlated with asthma severity and granzyme B/perforin expression of CD4(+) iNKT cells. Furthermore, it could be abrogated by either inhibition of the granzyme B-/perforin-dependent cell death pathway or oral corticosteroid administration. Altogether, these findings suggest that increased cytotoxicity of CD4(+) iNKT cells against Treg might contribute to dysfunctional cellular interactions in AA.