MRC National Institute for Medical Research, London
Science for Health
Learning about tuberculosis immunity from adversity
29 September 2009
Protective immunity to tuberculosis (TB) is ill understood, partly because of the difficulties in defining protected and at-risk groups. Antiretroviral treatment (ART) reduces the risk of TB in HIV infected people. Longitudinal analysis of a highly susceptible group (HIV infected people with low CD4 counts) who become less susceptible (as a result of ART) therefore is a novel approach to the definition of protective mechanisms in human TB. This study was conducted in South Africa which has one of the highest HIV-TB co-infection rates in the world.
Katalin Wilkinson works at the University of Cape Town but is also a member of the group of Robert Wilkinson (pictured) in NIMR's Division of Mycobacterial Research. Katalin has shown that in the context of overall improved TB antigen specific T cell responses it is the central memory rather than effector memory response that best correlates with decreased susceptibility. This has important implications for vaccine design, as well as monitoring vaccine efficiency. Peripheral blood mononuclear cells were obtained on day 0, weeks 2, 4, 12, 24, 36 and 48 of antiretroviral therapy and were stimulated with Purified Protein Derivative (PPD), followed by flow cytometry to analyse surface markers and intracellular cytokines. CD4+ T cells significantly increased during follow up and the viral load fell to undetectable levels in each patient, indicating successful immune restoration. Central memory CD27+CD45RA- and CD27+CCR5- CD4+ cells expanded by 12 weeks, followed by naive CD27+CD45RA+ cells at 36 weeks. Terminally differentiated effector CD4+CD27-CCR7- cells decreased by 12 weeks, paralleled by a proportional decline of PPD specific CD4+IFN-γ+ cells.
The work shows how knowledge can be gained by following carefully defined patients longitudinally over time. The results are in line with what many now believe, that rapid effector T cell responses are a poor correlate of protection against tuberculosis and that more attention should be given to the memory T cell subset.
Robert Wilkinson
Concept diagram explaining the dynamics of the reconstituting T cells during cART, corrected for CD4 counts
The proportion of Naïve, central memory and terminally differentiated effector T cells was summed at each timepoint for each patient, normalised to 100% and multiplied by the CD4 count of each respective patient at that timepoint. The diagram illustrates that while effector T cells proportionally decline during cART, the actual numbers increase.
Original article
The research findings are published in full in:
Wilkinson, K. A., R. Seldon, G. Meintjes, M. X. Rangaka, W. A. Hanekom, G. Maartens, and R. J. Wilkinson (2009)
Dissection of regenerating T-Cell responses against tuberculosis in HIV-infected adults sensitized by Mycobacterium tuberculosis
American Journal of Respiratory and Critical Care Medicine, 180:674-683. Pubmed abstract.
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