Functional capacity of Mycobacterium tuberculosis-specific T cell responses in humans is associated with mycobacterial load

• Published in: The Journal of immunology (1950) Vol. 187; no. 5; pp. 2222 - 2232
• Main Authors: Day, Cheryl L, Abrahams, Deborah A, Lerumo, Lesedi, Janse van Rensburg, Esme, Stone, Lynnett, O'rie, Terrence, Pienaar, Bernadette, de Kock, Marwou, Kaplan, Gilla, Mahomed, Hassan, Dheda, Keertan, Hanekom, Willem A
• Format: Journal Article
• Language: English
• Published: United States 01.09.2011
• Subjects: Adolescent; Adult; Bacterial Load; Cell Proliferation; Cell Separation; Cytokines - biosynthesis; Disease Progression; Female; Flow Cytometry; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Mycobacterium tuberculosis - immunology; T-Lymphocyte Subsets - immunology; T-Lymphocytes - immunology; Tuberculosis - immunology; Tuberculosis - microbiology; Young Adult
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1101122

High Ag load in chronic viral infections has been associated with impairment of Ag-specific T cell responses; however, the relationship between Ag load in chronic Mycobacterium tuberculosis infection and functional capacity of M. tuberculosis-specific T cells in humans is not clear. We compared M. tuberculosis-specific T cell-associated cytokine production and proliferative capacity in peripheral blood from adults with progressively higher mycobacterial loads-that is, persons with latent M. tuberculosis infection (LTBI), with smear-negative pulmonary tuberculosis (TB), and smear-positive TB. Patients with smear-positive TB had decreased polyfunctional IFN-γ(+)IL-2(+)TNF-α(+) and IL-2-producing specific CD4 T cells and increased TNF-α single-positive cells, when compared with smear-negative TB and LTBI. TB patients also had increased frequencies of M. tuberculosis-specific CD8 T cells, compared with LTBI. M. tuberculosis-specific CD4 and CD8 T cell proliferative capacity was profoundly impaired in individuals with smear-positive TB, and correlated positively with ex vivo IFN-γ(+)IL-2(+)TNF-α(+) CD4 T cells, and inversely with TNF-α single-positive CD4 T cells. During 6 mo of anti-TB treatment, specific IFN-γ(+)IL-2(+)TNF-α(+) CD4 and CD8 T cells increased, whereas TNF-α and IFN-γ single-positive T cells decreased. These results suggest progressive impairment of M. tuberculosis-specific T cell responses with increasing mycobacterial load and recovery of responses during therapy. Furthermore, these data provide a link between specific cytokine-producing subsets and functional capacity of M. tuberculosis-specific T cells, and between the presence of specific CD8 T cells ex vivo and active TB disease. These data have potentially significant applications for the diagnosis of TB and for the identification of T cell correlates of TB disease progression.