Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70

Abstract

Various subsets of invariant natural killer T (iNKT) cells with different cytokine productions develop in the mouse thymus, but the factors driving their differentiation remain unclear. Here we show that hypomorphic alleles of Zap70 or chemical inhibition of Zap70 catalysis leads to an increase of IFN-γ-producing iNKT cells (NKT1 cells), suggesting that NKT1 cells may require a lower TCR signal threshold. Zap70 mutant mice develop IL-17-dependent arthritis. In a mouse experimental arthritis model, NKT17 cells are increased as the disease progresses, while NKT1 numbers negatively correlates with disease severity, with this protective effect of NKT1 linked to their IFN-γ expression. NKT1 cells are also present in the synovial fluid of arthritis patients. Our data therefore suggest that TCR signal strength during thymic differentiation may influence not only IFN-γ production, but also the protective function of iNKT cells in arthritis.

Recent advances in iNKT cell development

“…Overall, this suggests a potential requirement for different TCR signal intensities in the development of each (Figure 2). In fact, two independent groups recently addressed this question by exploiting the SKG mouse model, in which TCR signaling is weakened because of a hypo-morphic ZAP70 allele 54,56 . Hence, both studies showed that weakened TCR signaling led to abrogation in NKT2 and, to a lesser extent, NKT17 cell development while not reducing NKT1 cell development.…”

NKT cells and the regulation of intestinal immunity: a two‐way street

“…For instance, in support of thymic commitment it has been shown that the TCR signal strength during thymic development can direct the differentiation of iNKT cells within specific functional subsets . Further to this, a variety of signalling molecules and transcription factors including Zap70, Bcl11b or Roquin has been shown to participate in the control of iNKT cell lineage differentiation . On the other hand, several lines of evidence suggest that iNKT cells can acquire functional capabilities in the periphery.…”

Hippo/Mst signaling coordinates cellular quiescence with terminal maturation in iNKT cell development and fate decisions

“…Recent evidence has identified altered TCR signal strength as a regulator of iNKT cell effector subset development, with decreased TCR signal strength leading to a predominance of iNKT1 cells, while strong TCR signal strength enhances iNKT2 and iNKT17 cell development (Tuttle et al, 2018; Zhao et al, 2018). The induction of Mob1 (Thr35) phosphorylation downstream of TCR/CD28 signaling occurred in an Mst1-dependent manner (Fig.…”