Abstract
Several immune-based assays have been suggested to differentiate latent from active tuberculosis (TB). However, their relative performance as well as their efficacy in HIV-infected persons, a highly at-risk population, remains unclear. In a study of 81 individuals, divided into four groups based on their HIV-1 status and TB disease activity, we compared the differentiation (CD27 and KLRG1), activation (HLA-DR), homing potential (CCR4, CCR6, CXCR3, and CD161) and functional profiles (IFNγ, IL-2, and TNFα) of Mycobacterium tuberculosis (Mtb)-specific CD4+ T cells using flow cytometry. Active TB disease induced major changes within the Mtb-responding CD4+ T cell population, promoting memory maturation, elevated activation and increased inflammatory potential when compared to individuals with latent TB infection. Moreover, the functional profile of Mtb-specific CD4+ T cells appeared to be inherently related to their degree of differentiation. While these specific cell features were all capable of discriminating latent from active TB, irrespective of HIV status, HLA-DR expression showed the best performance for TB diagnosis [area-under-the-curve (AUC) = 0.92, 95% CI: 0.82–1.01, specificity: 82%, sensitivity: 84% for HIV− and AUC = 0.99, 95% CI: 0.98–1.01, specificity: 94%, sensitivity: 93% for HIV+]. In conclusion, these data support the idea that analysis of T cell phenotype can be diagnostically useful in TB.
Highlights
With almost 2 million deaths and over 10 million new cases in 2015, tuberculosis (TB) remains a global health priority
To better understand the profile of Mycobacterium tuberculosis (Mtb)-specific T cell responses, we first defined the frequency of Mtb-specific CD4+ T cells in 81 participants grouped according to HIV-1 and TB status (Table 1)
CD27 expression was reduced on CMVspecific IFNγ+ CD4+ T cells in HIV-infected persons when compared to HIV-uninfected (49% in latent tuberculosis infection (LTBI) and 26% in active TB (aTB)) (Figure 2C). These results show that aTB disease associates with the activation and memory differentiation of Mtb-specific CD4+ T cells; these cellular features would be consistent with ongoing bacterial replication
Summary
With almost 2 million deaths and over 10 million new cases in 2015, tuberculosis (TB) remains a global health priority. In southern Africa, the HIV pandemic fuels the TB burden, where over 50% of new TB cases are HIV associated [1]. While being of relatively high specificity, all these techniques require either sputum or a specimen from the site of disease. This makes diagnosis of pulmonary TB in patients with negative sputum smears or a non-productive cough, or extrapulmonary TB, difficult. This limitation is especially relevant in HIV-infected persons, where immunosuppression associates with reduced cavitation, limiting the sensitivity of sputum-based assays [5]. Alternate host response-based diagnostics are much needed to distinguish latent tuberculosis infection (LTBI) from active TB (aTB), for those most at risk, such as HIV-1-infected individuals
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