Following on from yesterday’s posting about central memory T cells, a new paper in the Journal of Infectious Diseases offers what may be a clearer view of the impact of the loss of this cell population in HIV infection. Cheryl Day and collaborators (from the University of KwaZulu Natal in Durban and Partners AIDS Research in Boston) investigated memory CD4 and CD8 T cell responses to Mycobacterium tuberculosis (MTB) in a cohort of individuals with HIV infection and latent (asymptomatic) TB, finding that cells producing IL-2 – a signature cytokine of central memory T cells – are depleted compared to cells producing TNF-alpha and interferon gamma or interferon gamma alone. Furthermore, they report an inverse correlation between HIV viral load and the proportion of IL-2-producing MTB-specific CD4 T cells, stating that the data “suggests that MTB-specific CD4 T cells in HIV-1-positive subjects may gradually lose IL-2 secretion capacity as HIV-1 disease progresses.” The authors note that further studies are required to identify the mechanisms contributing to the impairment of MTB-specific T cell responses in people with HIV, and the data also suggest that more studies of the impact of antiretroviral therapy on the functional profile of MTB-specific T cell responses are needed.
The Journal of Infectious Diseases 2008;197:000–000
DOI: 10.1086/529048
MAJOR ARTICLE
Cheryl L. Day,1,3,4,a Nompumelelo Mkhwanazi,1 Sharon Reddy,1 Zenele Mncube,1 Mary van der Stok,1 Paul Klenerman,2 and Bruce D. Walker1,3,4,5
1HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu Natal, Durban, South Africa; 2Nuffield Department of Medicine, The Peter Medawar Building for Pathogen Research, Oxford University, Oxford, United Kingdom; 3Partners AIDS Research Center, Massachusetts General Hospital, and 4Division of AIDS, Harvard Medical School, Boston, Massachusetts; and 5Howard Hughes Medical Institute, Chevy Chase, Maryland
Background. The human immunodeficiency virus type 1 (HIV-1) epidemic is associated with a significant increase in the incidence of tuberculosis (TB); however, little is known about the quality of Mycobacterium tuberculosis (MTB)–specific cellular immune responses in coinfected individuals.
Methods. A total of 137 HIV-1–positive individuals in Durban, South Africa, were screened with the use of overlapping peptides spanning Ag85A, culture filtrate protein 10 (CFP-10), early secretory antigen target 6 (ESAT-6), and TB10.4, in an interferon (IFN)–γ enzyme-linked immunospot (ELISPOT) assay. Intracellular cytokine staining for MTB-specific production of IFN-γ, tumor necrosis factor (TNF)–α, and interleukin (IL)–2 was performed, as was ex vivo phenotyping of memory markers on MTB-specific T cells.
Results. A total of 41% of subjects responded to ESAT-6 and/or CFP-10, indicating the presence of latent MTB infection. The proportion of MTB-specific IFN-γ+/TNF-α+ CD4+ cells was significantly higher than the proportion of IFN-γ+/IL-2+ CD4+ cells (p=.0220), and the proportion of MTB-specific IL-2–secreting CD4 cells was inversely correlated with the HIV-1 load (p=.0098). MTB-specific CD8 T cells were predominately IFN-γ+/TNF-α+/IL-2−. Ex vivo memory phenotyping of MTB-specific CD4 and CD8 T cells indicated an early to intermediate differentiated phenotype for the population of effector memory cells.
Conclusions. Polyfunctional MTB-specific CD4 and CD8 T cell responses are maintained in the peripheral blood of HIV-1–positive individuals, in the absence of active disease, and the functional capacity of these responses is affected by HIV-1 disease status.
The Journal of Infectious Diseases 2008;197:000–000
DOI: 10.1086/529049
EDITORIAL COMMENTARY
T Cells and Tuberculosis: Beyond Interferon-γ
Ajit Lalvani and Kerry A. Millington
Tuberculosis Immunology Group, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom
Received 18 December 2007; accepted 19 December 2007; electronically published 4 March 2008.
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