Cytokine polarized natural killer T cells modulate effector T cell function in leprosy

Leprosy, caused by Mycobacterium leprae, presents a clinical spectrum reflecting distinct host immune responses. Tuberculoid/borderline tuberculoid (TT/BT) patients exhibit Th1-skewed granulomatous immunity with restricted bacillary spread, whereas lepromatous/borderline lepromatous (LL/BL) patients display Th2 dominant responses with disseminated disease and high bacterial load. While Th1/Th2 polarization is well established, the contribution of Natural Killer T (NKT) cells to disease immunopathogenesis is not fully understood. NKT cells, identified by CD3 + CD161+ phenotype and semi-invariant TCRs, rapidly secrete cytokines upon lipid antigen recognition and can influence conventional T cell polarization. In this study, we examined NKT cell frequency, cytokine profiles and chemokine receptor expression in leprosy patients. BT/TT patients showed increased frequencies of IFN-γ-producing NKT cells, while BL/LL patients had elevated IL-4-producing NKT and invariant NKT (iNKT) cells. Sequential stimulation and cytokine-blocking experiments demonstrated that NKT-derived IFN-γ enhances Th1 responses in BT/TT, whereas IL-4 suppresses Th1 activity in BL/LL patients. Furthermore, BL/LL NKT cells showed upregulated CCR4, CCR5, and CXCR3, corresponding to Th2 bias, while BT/TT NKT cells had increased CCR6, consistent with Th1 responses. These findings demonstrate that cytokine-polarized NKT cells critically modulate effector T cell function in leprosy, shaping the clinical heterogeneity. Our study highlights NKT cells as potential immunoregulatory targets and suggests that modulating lipid antigen-responsive NKT subsets may offer novel therapeutic strategies for leprosy and related chronic infections.