IFNG-mediated immune responses enhance autophagy against Mycobacterium tuberculosis antigens in patients with active tuberculosis

Abstract

Protective immunity against Mycobacterium tuberculosis (Mtb) requires IFNG. Besides, IFNG-mediated induction of autophagy suppresses survival of virulent Mtb in macrophage cell lines. We investigated the contribution of autophagy to the defense against Mtb antigen (Mtb-Ag) in cells from tuberculosis patients and healthy donors (HD). Patients were classified as high responders (HR) if their T cells produced significant IFNG against Mtb-Ag; and low responders (LR) when patients showed weak or no T cell responses to Mtb-Ag. The highest autophagy levels were detected in HD cells whereas the lowest quantities were observed in LR patients. Interestingly, upon Mtb-Ag stimulation, we detected a positive correlation between IFNG and MAP1LC3B-II/LC3-II levels. Actually, blockage of Mtb-Ag-induced IFNG markedly reduced autophagy in HR patients whereas addition of limited amounts of IFNG significantly increased autophagy in LR patients. Therefore, autophagy collaborates with human immune responses against Mtb in close association with specific IFNG secreted against the pathogen.

Keywords:

• autophagy
• cytokines
• defense
• IFNG
• immune response
• patients
• tuberculosis

Abbreviations:

• AG, antigen
• ATG, autophagy-related
• FBS, fetal bovine serum
• GAPDH, glyceraldehyde-3-phosphate dehydrogenase
• GTP, guanosine triphosphate
• HD, healthy donors
• HR TB, high-responder tuberculosis patient
• IFNG, interferon gamma
• IL, Interleukin
• LC3, microtubule-associated protein 1A/1B-light chain 3
• LR TB, low-responder tuberculosis patients
• mAb, monoclonal antibody
• Mtb-Ag, Mycobacterium tuberculosis antigen
• PBS, phosphate-buffered saline
• PBMC, peripheral blood mononuclear cells
• rIFNG, recombinant IFNG
• SLAM, signaling lymphocytic activation molecule
• TB, tuberculosis
• Th, T helper

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgements

We thank Dr. Peter Barnes for insightful discussions.

Funding

This investigation received financial support from the Agencia Nacional de Promoción Científica y Tecnológica (PAE-PID-2007-00127, PAE-PICT-2007-02332 and PICT-2011-0240 to V. E. G; PICT-2008-0192 and PICT-2011 to M.I.C); the University of Buenos Aires (20020100100221 to V.E.G.); Consejo Nacional de Investigaciones Científicas y Tecnológicas (PIP 2012-2014 to V.E.G.); and Universidad Nacional de Cuyo (SECYPT to M.I.C.). M.I.C and V.E.G. are members of the Researcher Career of CONICET (Argentina).

Supplemental Material

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