Reciprocity between Regulatory T Cells and Th17 Cells: Relevance to Polarized Immunity in Leprosy

Soumi Sadhu; Binod Kumar Khaitan; Beenu Joshi; Utpal Sengupta; Arvind Kumar Nautiyal; Dipendra Kumar Mitra

doi:10.1371/journal.pntd.0004338

Reciprocity between Regulatory T Cells and Th17 Cells: Relevance to Polarized Immunity in Leprosy

PLoS Negl Trop Dis. 2016 Jan 11;10(1):e0004338. doi: 10.1371/journal.pntd.0004338. eCollection 2016 Jan.

Authors

Soumi Sadhu¹, Binod Kumar Khaitan², Beenu Joshi³, Utpal Sengupta⁴, Arvind Kumar Nautiyal¹, Dipendra Kumar Mitra¹

Affiliations

¹ Department of Transplant Immunology and Immunogenetics, AIIMS, New Delhi, India.
² Department of Dermatology and Venereology, AIIMS, New Delhi, India.
³ Immunology Division, National Jalma Institute for Leprosy and Other Mycobacterial Diseases, ICMR, Agra, India.
⁴ Stanley Browne Research Laboratory, The Leprosy Mission, Shahdara, New Delhi, India.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antibodies
Antigens, Bacterial
Biomarkers
Cells, Cultured
Disease Susceptibility
Female
Humans
Interleukin-10 / genetics
Interleukin-10 / metabolism
Leprosy / immunology*
Leprosy / microbiology
Leukocytes, Mononuclear / physiology
Male
Middle Aged
Mycobacterium leprae / immunology
Mycobacterium leprae / metabolism
T-Lymphocytes, Regulatory / physiology*
Th17 Cells / physiology*
Young Adult

Substances

Antibodies
Antigens, Bacterial
Biomarkers
Interleukin-10

Grants and funding

This work was supported by the Indian Council of Medical Research, Government of India [Grant No. 5/8/3(11)/2009-ECD-I(A)]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.