title: Reciprocity between Regulatory T Cells and Th17 Cells: Relevance to Polarized Immunity in Leprosy.
abstract: T cell defect is a common feature in lepromatous or borderline lepromatous leprosy (LL/BL) patients in contrast to tuberculoid or borderline tuberculoid type (TT/BT) patients. Tuberculoid leprosy is characterized by strong Th1-type cell response with localized lesions whereas lepromatous leprosy is hallmarked by its selective Mycobacterium leprae specific T cell anergy leading to disseminated and progressive disease. FoxP3+ Regulatory T cells (Treg) which are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases also dampen proinflammatory T cells that include T helper 17 (Th17) cells. This study is aimed at evaluating the role of Treg cells in influencing other effector T cells and its relationship with the cytokine polarized state in leprosy patients. Peripheral blood mononuclear cells from of BT/TT (n = 15) and BL/LL (n = 15) patients were stimulated with M. leprae antigen (WCL) in presence of golgi transport inhibitor monensin for FACS based intracellular cytokine estimation. The frequency of Treg cells showed >5-fold increase in BL/LL in comparison to BT/TT and healthy contacts. These cells produced suppressive cytokine, IL-10 in BL/LL as opposed to BT/TT (p = 0.0200) indicating their suppressive function. The frequency of Th17 cells (CD4, CD45RO, IL-17) was, however, higher in BT/TT. Significant negative correlation (r = -0.68, P = 0.03) was also found between IL-10 of Treg cells and IL-17+ T cells in BL/LL. Blocking IL-10/TGF-β restored the IL-17+ T cells in BL/LL patients. Simultaneously, presence of Th17 related cytokines (TGF-β, IL-6, IL-17 and IL-23) decreased the number of FoxP3+ Treg cells concomitantly increasing IL-17 producing CD4+ cells in lepromatous leprosy. Higher frequency of Programmed Death-1/PD-1+ Treg cells and its ligand, PDL-1 in antigen presenting cells (APCs) was found in BL/LL patients. Inhibition of this pathway led to rescue of IFN-γ and IL-17 producing T cells. Results indicate that Treg cells are largely responsible for the kind of immunosuppression observed in BL/LL patients. This study also proves that Treg cells are profoundly affected by the cytokine milieu and this property may be utilized for benefit of the host.
authors.affiliation: Department of Transplant Immunology and Immunogenetics, AIIMS, New Delhi, India.
authors.forename: Soumi
authors.initials: S
authors.lastname: Sadhu
authors.affiliation: Department of Dermatology and Venereology, AIIMS, New Delhi, India.
authors.forename: Binod Kumar
authors.initials: BK
authors.lastname: Khaitan
authors.affiliation: Immunology Division, National Jalma Institute for Leprosy and Other Mycobacterial Diseases, ICMR, Agra, India.
authors.forename: Beenu
authors.initials: B
authors.lastname: Joshi
authors.affiliation: Stanley Browne Research Laboratory, The Leprosy Mission, Shahdara, New Delhi, India.
authors.forename: Utpal
authors.initials: U
authors.lastname: Sengupta
authors.affiliation: Department of Transplant Immunology and Immunogenetics, AIIMS, New Delhi, India.
authors.forename: Arvind Kumar
authors.initials: AK
authors.lastname: Nautiyal
authors.affiliation: Department of Transplant Immunology and Immunogenetics, AIIMS, New Delhi, India.
authors.forename: Dipendra Kumar
authors.initials: DK
authors.lastname: Mitra
mesh_terms: D000328:Adult; D000906:Antibodies; D000942:Antigens, Bacterial; D015415:Biomarkers; D002478:Cells, Cultured; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D007918:Leprosy / Q000276:immunology* / Q000382:microbiology; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009166:Mycobacterium leprae / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D058504:Th17 Cells / Q000502:physiology*; D055815:Young Adult
chemical_list: D000906:Antibodies; D000942:Antigens, Bacterial; D015415:Biomarkers; D016753:Interleukin-10