Functional and Activation Profiles of Mucosal-Associated Invariant T Cells in Patients With Tuberculosis and HIV in a High Endemic Setting

Abstract

Background: MAIT cells are non-classically restricted T lymphocytes that recognize and rapidly respond to microbial metabolites or cytokines and have the capacity to kill bacteria-infected cells. Circulating MAIT cell numbers generally decrease in patients with active TB and HIV infection, but findings regarding functional changes differ.Methods: We conducted a cross-sectional study on the effect of HIV, TB, and HIV-associated TB (HIV-TB) on MAIT cell frequencies, activation and functional profile in a high TB endemic setting in South Africa. Blood was collected from (i) healthy controls (HC, n = 26), 24 of whom had LTBI, (ii) individuals with active TB (aTB, n = 36), (iii) individuals with HIV infection (HIV, n = 50), 37 of whom had LTBI, and (iv) individuals with HIV-associated TB (HIV-TB, n = 26). All TB participants were newly diagnosed and sampled before treatment, additional samples were also collected from 18 participants in the aTB group after 10 weeks of TB treatment. Peripheral blood mononuclear cells (PBMC) stimulated with BCG-expressing GFP (BCG-GFP) and heat-killed (HK) Mycobacterium tuberculosis (M.tb) were analyzed using flow cytometry. MAIT cells were defined as CD3+ CD161+ Vα7.2+ T cells.Results: Circulating MAIT cell frequencies were depleted in individuals with HIV infection (p = 0.009). MAIT cells showed reduced CD107a expression in aTB (p = 0.006), and reduced IFNγ expression in aTB (p < 0.001) and in HIV-TB (p < 0.001) in response to BCG-GFP stimulation. This functional impairment was coupled with a significant increase in activation (defined by HLA-DR expression) in resting MAIT cells from HIV (p < 0.001), aTB (p = 0.019), and HIV-TB (p = 0.005) patients, and higher HLA-DR expression in MAIT cells expressing IFNγ in aTB (p = 0.009) and HIV-TB (p = 0.002) after stimulation with BCG-GFP and HK-M.tb. After 10 weeks of TB treatment, there was reversion in the observed functional impairment in total MAIT cells, with increases in CD107a (p = 0.020) and IFNγ (p = 0.010) expression.Conclusions: Frequencies and functional profile of MAIT cells in response to mycobacterial stimulation are significantly decreased in HIV infected persons, active TB and HIV-associated TB, with a concomitant increase in MAIT cell activation. These alterations may reduce the capacity of MAIT cells to play a protective role in the immune response to these two pathogens.

It Takes a Village: The Multifaceted Immune Response to Mycobacterium tuberculosis Infection and Vaccine-Induced Immunity

“…MAIT cells are T cells that are similarly non-classically restricted but with a propensity for mucosal homing, recognizing antigens presented on MR1 with rapid response capabilities and the functional capacity to kill infected cells ( 296 , 427 , 428 ). However, their active role is somewhat confusing as some clinical data demonstrate that individuals with TB have decreased numbers of circulating MAIT cells with reduced activation ( 429 ), whereas others are detected with tetramers at similar frequencies in peripheral blood from TB-infected and uninfected individuals ( 427 ). In mouse models of TB challenge, MAIT cells have been shown to delay T-cell priming early during challenge but are efficient targets of host-directed therapies ( 428 ), making them an interesting target in vaccine and drug therapy strategies.…”

Relevant mechanisms of MAIT cells involved in the pathogenesis of periodontitis

“…Programmed death 1 (PD-1) and GrB were higher than their preinfection rate ( Lal et al., 2020 ). The longer the course of the disease, the more irreversibly damaged the immune function of MAIT cells becomes; in addition, their immune response and function against other pathogens, such as Mycobacterium tuberculosis, are significantly reduced ( Balfour et al., 2021 ).…”

Current Perspectives and Challenges of MAIT Cell-Directed Therapy for Tuberculosis Infection

“…A rather surprising outcome from another study showed that priming MAIT cells with 5-OP-RU in Mtbinfected rhesus macaques did not lead to expansion of the population, failed to stimulate cytokine production, and instead upregulated programmed death-1 (PD-1), normally associated with T cell exhaustion [88]. This dramatic reduction in circulating MAIT cell is also witnessed with HIV infection and HIV-TB coinfection and importantly, these numbers do not recover despite successful treatment, conceivably influencing the ability to withstand future opportunistic infections [59,89]. This suggests that MAIT cell replenishment could be a useful strategy to prevent disease relapse or other secondary infections.…”