Background Approximately one-third of the world's population is infected with Mycobacterium tuberculosis (MTB), mostly as latent tuberculosis infection (LTBI). HIV co-infection confers the single greatest risk of progression to active tuberculosis (TB) and thus provides an opportunity to study the host–pathogen interaction in LTBI. The stage of TB disease and effect of advancing HIV infection should be reflected in the phenotype and function of MTB-specific T cells.
Aims To compare MTB-specific CD4+ and CD8+ T cell responses in donors from four clinical phenotypes (TB/HIV, TB, LTBI/HIV and LTBI) and test whether TB in the context of HIV is a spectrum of disease dependent on mycobacterial load consequent upon advancing immunosuppression and viraemia.
Methods Donors (n=34) with or without HIV co-infection were carefully selected for active TB or LTBI. Peripheral blood mononuclear cells (PBMCs) were stimulated overnight with purified protein derivative (PPD) or a combination of MTB-specific antigens. An 11-colour intracellular cytokine secretion assay was used to assess CD3, CD4, CD8, IFN-γ, IL-2 and TNF-α expression.
Results The proportion of participants with a CD8+ PPD-specific IFN-γ (p=0.001) or TNF-α (p=0.006) response closely mirrored stage of TB disease, whereas the equivalent CD4 response was unaffected. The proportion of CD4+ and CD8+ PPD-specific cells increased with TB stage for IFN-γ and TNF-α, but did not increase in HIV/TB co-infection compared with TB (Abstract S43 figure 1). When individual cytokine subsets were examined, the percentage of CD4+ and CD8+ cells producing IFN-γ, TNF-α or dual responses was higher in all participants with TB compared with LTBI. CD4+IL-2+ cells were reduced by HIV co-infection, especially IFN-γ+/IL-2+ cells (p=0.008) and this was apparent as a proportion of total cytokine response (p=0.016).
Conclusions The proportion of CD8+ IFN-γ or TNF-α responders was a more sensitive indicator of TB stage than CD4 responses. CD4+ IL-2 responses were vulnerable to HIV co-infection, possibly affecting CD8+ IFN-γ and TNF-α responses at high viral loads, increasing susceptibility to active TB. These immune correlates of the TB spectrum and the MTB-specific T-cell deficiencies caused by HIV co-infection are important in rationalising treatment of co-infection as well as testing new vaccines and therapeutics.