Elevated IL-6R on CD4+ T cells promotes IL-6 driven Th17 cell responses in patients with T1R leprosy reactions.

Th17 cells play vital role during pathogenesis of leprosy reactions. Previously, we have reported that IL-23 is involved in Th17 cells differentiation. Subsequently, our group also showed that IL-6 induces Th17 cell differentiation along with TGF-ß in leprosy reactions. Here, we next asked the question that whether IL-6 or IL-23 induced Th17 cells are different in nature? In this study, Type 1 Reactions (T1R) showed significantly (p < 0.001) higher percentage of IL-17A producing CD4+IL6R+ T cells as compared to non-reaction (NR) patients. Furthermore, recombinant IL-6, IL-23 and TGF-ß promoted IL-17A secretion by CD4+IL6R+ T cells. Subsequently, IL-6R and IL-23R blocking experiments showed significantly (p < 0.002) down regulated IL-17A in T1R reaction as compared to NR leprosy patients. The present study for the first time establishes that pathogenic Th17 cells produce IL-17 in an IL-6 dependent manner in leprosy T1R reactions. Thus, present approaches that specifically target Th17 cells and/or the cytokines that promote their development, such as IL-6, TGF-ß and IL-23A may provide more focused treatment strategies for the management of Mycobacterium leprae and its reactions.

Interleukin-10 Producing Regulatory B Cells Transformed CD4+CD25- Into Tregs and Enhanced Regulatory T Cells Function in Human Leprosy.

Regulatory B cells (Bregs) are known to exhibit their regulatory functions through interleukin-10 (IL-10) cytokine which suppress inflammation. There are only a few studies explaining the phenotype and functioning of these cells in contribution to host immunity in leprosy. Here, we evaluated the role of IL-10 producing Bregs in the pathogenesis of leprosy and assessed their immunoregulatory effects on Tregs and effector T cells. We found an increased frequency of Bregs and increased expression of their immune modulatory molecules (IL-10, FoxP3, and PDL-1) in leprosy patients. The potential immunoregulatory mechanism of Bregs was also investigated using MACS sorted Teff (CD4+CD25-) and Treg (CD4+CD25+) cells were cocultured with Bregs to elucidate the effects of Bregs on effector T and regulatory T cells. Cell coculture results showed that purified Bregs cells from leprosy patients convert CD4+CD25- cells into CD4+CD25+ cells. Cell coculture experiments also demonstrated that leprosy derived IL-10 producing Bregs enhance FoxP3 and PD-1 expression in Tregs and enhanced Tregs activity. Blocking of IL-10 receptor confirmed that IL-10 producing Breg has immunomodulatory effect on Tregs and effector T cells as effector T cells are not converted into Tregs and enhanced expression of FoxP3 and PD-1 was not observed on Tregs. Collectively, these findings demonstrate that IL-10 producing Breg cells play an important mechanism in controlling the immunopathogenesis of leprosy and have an immunomodulatory effect on Tregs and effector T cells. Our findings may pave way for novel targets of IL-10 producing Bregs for immunotherapy in leprosy patients.