Distinct phenotype and effector function of CD4 coreceptor disparate iNKT cell subsets

The role of coreceptors in iNKT cell development and effector functions, however, remains unclear. Here, we show that CD4 expression correlates with the subset identity of iNKT cells, specifically unveiling a dichotomy of CD4 coreceptors among IFNγ-producing iNKT cells that we refer to as NKT1.4+ and NKT1.4– cells, based on CD4 expression.

These CD4 disparate NKT1 cells markedly differed in their gene transcription profiles, surface phenotypes, and effector functions, revealing a CD4 coreceptor-associated divergence in iNKT cells. Moreover, CD4 expression was associated with enhanced TCR signaling in iNKT cells, such that CD4-deficiency heavily disturbed their generation and differentiation in the thymus. Collectively, these results reveal a previously unappreciated association between CD4 coreceptor expression and iNKT effector function, establishing CD4 as a functional marker in iNKT cell biology.