title: A subset of circulating blood mycobacteria-specific CD4 T cells can predict the time to Mycobacterium tuberculosis sputum culture conversion.
abstract: We investigated 18 HIV-negative patients with MDR-TB for M. tuberculosis (Mtb)- and PPD-specific CD4 T cell responses and followed them over 6 months of drug therapy. Twelve of these patients were sputum culture (SC) positive and six patients were SC negative upon enrollment. Our aim was to identify a subset of mycobacteria-specific CD4 T cells that would predict time to culture conversion. The total frequency of mycobacteria-specific CD4 T cells at baseline could not distinguish patients showing positive or negative SC. However, a greater proportion of late-differentiated (LD) Mtb- and PPD-specific memory CD4 T cells was found in SC positive patients than in those who were SC negative (p = 0.004 and p = 0.0012, respectively). Similarly, a higher co-expression of HLA-DR+ Ki67+ on Mtb- and PPD-specific CD4 T cells could also discriminate between sputum SC positive versus SC negative (p = 0.004 and p = 0.001, respectively). Receiver operating characteristic (ROC) analysis revealed that baseline levels of Ki67+ HLA-DR+ Mtb- and PPD-specific CD4 T cells were predictive of the time to sputum culture conversion, with area-under-the-curve of 0.8 (p = 0.027). Upon treatment, there was a significant decline of these Ki67+ HLA-DR+ T cell populations in the first 2 months, with a progressive increase in mycobacteria-specific polyfunctional IFNγ+ IL2+ TNFα+ CD4 T cells over 6 months. Thus, a subset of activated and proliferating mycobacterial-specific CD4 T cells (Ki67+ HLA-DR+) may provide a valuable marker in peripheral blood that predicts time to sputum culture conversion in TB patients at the start of treatment.
authors.affiliation: Division of Immunology, Institute of Infectious Disease and Molecular Medicine and National Health Laboratory Services, University of Cape Town, Cape Town, South Africa.
authors.forename: Catherine
authors.initials: C
authors.lastname: Riou
authors.affiliation: Division of Immunology, Institute of Infectious Disease and Molecular Medicine and National Health Laboratory Services, University of Cape Town, Cape Town, South Africa.
authors.forename: Clive M
authors.initials: CM
authors.lastname: Gray
authors.affiliation: National Institute for Communicable Diseases, National Health Laboratory Services, Johannesburg, South Africa.
authors.forename: Masixole
authors.initials: M
authors.lastname: Lugongolo
authors.affiliation: National Institute for Communicable Diseases, National Health Laboratory Services, Johannesburg, South Africa.
authors.forename: Thabisile
authors.initials: T
authors.lastname: Gwala
authors.affiliation: Division of Immunology, Institute of Infectious Disease and Molecular Medicine and National Health Laboratory Services, University of Cape Town, Cape Town, South Africa.
authors.forename: Agano
authors.initials: A
authors.lastname: Kiravu
authors.affiliation: Right to Care and the Clinical HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Pamela
authors.initials: P
authors.lastname: Deniso
authors.affiliation: Right to Care and the Clinical HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Lynsey
authors.initials: L
authors.lastname: Stewart-Isherwood
authors.affiliation: National Institute for Communicable Diseases, National Health Laboratory Services, Johannesburg, South Africa.
authors.forename: Shaheed Vally
authors.initials: SV
authors.lastname: Omar
authors.affiliation: Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Martin P
authors.initials: MP
authors.lastname: Grobusch
authors.affiliation: National Institute for Communicable Diseases, National Health Laboratory Services, Johannesburg, South Africa.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Coetzee
authors.affiliation: Right to Care and the Clinical HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Francesca
authors.initials: F
authors.lastname: Conradie
authors.affiliation: National Institute for Communicable Diseases, National Health Laboratory Services, Johannesburg, South Africa.
authors.forename: Nazir
authors.initials: N
authors.lastname: Ismail
authors.affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute at the International Center for Public Health, Newark, New Jersey, United States of America.
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
authors.affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute at the International Center for Public Health, Newark, New Jersey, United States of America.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Fallows
mesh_terms: D000328:Adult; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D015331:Cohort Studies; D005260:Female; D006678:HIV / Q000302:isolation & purification; D015658:HIV Infections / Q000175:diagnosis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000276:immunology*; D013183:Sputum / Q000187:drug effects / Q000276:immunology / Q000382:microbiology*; D014376:Tuberculosis / Q000188:drug therapy / Q000276:immunology*