CD4-CD8-αβ and γδ T Cells Display Inflammatory and Regulatory Potentials during Human Tuberculosis

Shabaana Khader,Melina B Pinheiro,Danielle M Vitelli-Avelar,Vicente P C P Toledo,Lis R Antonelli,Olindo A Martins-Filho,Silvana Spindola-De-Miranda,Renato Sathler-Avelar,Tânia M P D Guimarães,Andrea Teixeira-Carvalho

doi:10.1371/journal.pone.0050923

Shabaana Khader, Melina B Pinheiro + Show 8 more

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https://doi.org/10.1371/journal.pone.0050923

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Abstract

T-cells play an important role controlling immunity against pathogens and therefore influence the outcome of human diseases. Although most T-lymphocytes co-express either CD4 or CD8, a smaller T-cell subset found the in the human peripheral blood that expresses the αβ or γδ T-cell-receptor (TCR) lacks the CD4 and CD8 co-receptors. These double negative (DN) T-cells have been shown to display important immunological functions in human diseases. To better understand the role of DN T-cells in human Mycobacterium tuberculosis, we have characterized their frequency, activation and cytokine profile in a well-defined group of tuberculosis patients, categorized as severe and non-severe based on their clinical status. Our data showed that whereas high frequency of αβ DN T-cells observed in M. tuberculosis-infected patients are associated with disease severity, decreased proportion of γδ DN T-cells are found in patients with severe tuberculosis. Together with activation of CD4+ and CD8+ T-cells, higher frequencies of both αβ and γδ DN T-cells from tuberculosis patients also express the chronic activation marker HLA-DR. However, the expression of CD69, an early activation marker, is selectively observed in DN T-cells. Interestingly, while αβ and γδ DN T-cells from patients with non-severe tuberculosis display a pro-inflammatory cytokine profile, characterized by enhanced IFN-γ, the γδ DN T-cells from patients with severe disease express a modulatory profile exemplified by enhanced interleukin-10 production. Overall, our findings suggest that αβ and γδ DN T-cell present disparate immunoregulatory potentials and seems to contribute to the development/maintenance of distinct clinical aspects of TB, as part of the complex immunological network triggered by the TB infection.

Highlights

A small proportion of T lymphocytes does not express either CD4 or CD8 and can be named double negative (DN) T-cells
When the comparison was done between HD and non-severe tuberculosis (nsTB) or severe tuberculosis (sTB) subgroups, the difference was seen between HD and sTB patients but not between HD and nsTB patients, indicating that this change happens due the severity of the disease
We establish that the DN lymphocyte population from M. tuberculosis-infected patients is composed of ab and cd DN T-cells that express a more pronounced activated and inflammatory profile compared to DN T-cells from non-infected individuals

Summary

Introduction

A small proportion of T lymphocytes does not express either CD4 or CD8 and can be named DN T-cells. The alteration in the proportions of this subpopulation has been demonstrated in infectious diseases such as leishmaniasis and Chagas, and its protective role has been described in mycobacterial infection [6,7,8]. The role of cd T-cells during M. tuberculosis infection was first described in 1989 [9]. Similar to the ab DN T-cell subpopulation, cd T-cells respond to M. tuberculosis antigens independently of major histocompatibility complex class II recognition [9,10]. The latter cell subpopulation was described to preferentially accumulate in inflammatory lesions and in necrotic areas of tuberculous lymphadenitis. In other infectious diseases, cd T-cells were associated with a regulatory profile exemplified by interleukin-10 production [6,7]

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