title: Functional capacity of Mycobacterium tuberculosis-specific T cell responses in humans is associated with mycobacterial load.
abstract: 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.
authors.affiliation: South African Tuberculosis Vaccine Initiative and School of Child and Adolescent Health, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa. cheryl.day@uct.ac.za
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Day
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Abrahams
authors.forename: Lesedi
authors.initials: L
authors.lastname: Lerumo
authors.forename: Esme
authors.initials: E
authors.lastname: Janse van Rensburg
authors.forename: Lynnett
authors.initials: L
authors.lastname: Stone
authors.forename: Terrence
authors.initials: T
authors.lastname: O'rie
authors.forename: Bernadette
authors.initials: B
authors.lastname: Pienaar
authors.forename: Marwou
authors.initials: M
authors.lastname: de Kock
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
authors.forename: Hassan
authors.initials: H
authors.lastname: Mahomed
authors.forename: Keertan
authors.initials: K
authors.lastname: Dheda
authors.forename: Willem A
authors.initials: WA
authors.lastname: Hanekom
mesh_terms: D000293:Adolescent; D000328:Adult; D058491:Bacterial Load; D049109:Cell Proliferation; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology*; D055815:Young Adult
chemical_list: D016207:Cytokines