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FoxP3⁺ Regulatory T Cells Suppress Effector T-Cell Function at Pathologic Site in Miliary Tuberculosis

¹ Department of Transplant Immunology and Immunogenetics, and ² Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, All India Institute of Medical Sciences, New Delhi, India; and ³ Institute of Genomics and Integrative Biology, Delhi, India

Correspondence and requests for reprints should be addressed to Dipendra K. Mitra, M.D., Ph.D., Division of Cellular Immunology, Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. E-mail: salilmitra1{at}yahoo.com

Rationale: The inadequacy of effector T-cell response in containment of tubercle bacilli is believed to result in the development of disseminated forms of tuberculosis (TB), such as miliary tuberculosis (MTB). Regulatory T cells (Treg) plausibly play a critical role in the immunopathogenesis of disseminated TB by suppression of effector immune response against Mycobacterium tuberculosis at the pathologic site(s). To understand the role of Treg cells in disseminated tuberculosis, we studied the frequency and function of Treg cells derived from the local disease site specimens (LDSS) of patients with TB pleural effusion and MTB as clinical models of contained and disseminated forms of disease, respectively.

Objectives: To (1) enumerate the frequency of Treg cells in bronchoalveolar lavage (BAL) fluid of patients with MTB and compare with that of peripheral blood, (2) study the role of Treg cells in suppression of local T-cell response, and (3) study the selective recruitment of Treg cells at the local disease site(s).

Methods: Flow cytometry, reverse transcriptase polymerase chain reaction, and 3-(4,5-dimethylthythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT)-based cell proliferation assay.

Measurements and Main Results: Frequency of Treg cells (CD4⁺CD25⁺FoxP3⁺) was significantly higher in LDSS in MTB along with higher levels of FoxP3 mRNA. Importantly, FoxP3⁺ Treg cells obtained from the BAL of patients with MTB predominantly produced IL-10 and could suppress the autologous T-cell proliferation in response to M. tuberculosis antigen.

Conclusions: Our results highlight the importance of Treg cells in suppression of effector immune response and their influence on bacillary dissemination, disease manifestation, and severity.

Key Words: regulatory T cells • FoxP3 • pleural effusion • BAL • miliary tuberculosis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Regulatory T cells play important roles in suppressing effector T cell function. Recruitment of T regulatory cells to sites of pathology may determine local immune reactions. What This Study Adds to the Field T regulatory cells appear to participate in the suppression of local immune responses in miliary tuberculosis.