Journal d'immunologie clinique et cellulaire
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Immunological Signatures Identifying Different Stages of Latent Mycobacterium tuberculosis Infection and Discriminating Latent from Active Tuberculosis in Humans

Kaatje Smits, Veronique Corbiere, Violette Dirix, Leila Mekkaoui, Chloe Wyndham-Thomas, Myriam Libin, Alexandra Dreesman, Marc Loyens, Marie- Christine Payen, Mahavir Singh, Camille Locht and Françoise Mascart

Objectives: One third of the world population is considered latently infected with Mycobacterium tuberculosis (LTBI) and sterilizing this reservoir of bacteria that may reactivate is required for tuberculosis (TB) elimination. The group of individuals with LTBI is heterogeneous with some of them being more at risk to develop TB disease than others. Improved diagnosis of subjects with LTBI is needed, allowing to differentiate subjects with LTBI from those with active TB, and to select among LTBI subjects those who are more at risk to develop active TB. We have characterized at the cellular level both the quantitative and qualitative T cell responses to different mycobacterial antigens in selected populations of infected subjects in order to identify new biomarkers that could help to identify M. tuberculosis-infected subjects and to stratify them in risk groups for reactivation of the infection.
Methods: lymphoblast frequencies and cytokine production (IFN-γ, TNF-α, IL-2) among CD4⁺ and CD8⁺ T cells were analyzed by flow cytometry after in vitro stimulation with the latency antigen heparin-binding haemagglutinin (HBHA) or early-secreted antigen Target-6 (ESAT-6) of peripheral blood mononuclear cells from clinically well characterized M. tuberculosis-infected humans (28 LTBI, 22 TB disease,12 controls). The LTBI group defined according to the Center for Disease Control guidelines was subdivided into QuantiFERON-TB Gold in-Tube (QFT) positive and negative subgroups.
Results: similar to TB patients, QFT⁺ LTBI subjects had higher proportions of HBHA-induced TNF-α^single+ CD4⁺ lymphocytes than QFT^- LTBI subjects (p<0.05). Compared to LTBI subjects, TB patients had higher frequencies of ESAT-6-induced CD8⁺ lymphoblasts (p<0.001), higher proportions of ESAT-6-induced IFN-γ⁺TNF-α⁺ CD4⁺ T lymphocytes (p<0.05), and lower proportions of HBHA-induced IFN-γ⁺TNF-α⁺IL-2⁺ (p<0.05) CD4⁺ T lymphocytes.
Conclusions: these data provide new biomarkers to discriminate active TB from LTBI, and more interestingly, help to identify LTBI subjects with increased likelihood to develop TB disease.