Abstract
Antigen-specific gamma-delta (γδ) T cells are important in exhibiting anti-mycobacterial immunity, but their role in latent tuberculosis (LTB) with diabetes mellitus (DM) or pre-DM (PDM) and non-DM comorbidities have not been studied. Thus, we have studied the baseline, mycobacterial (PPD, WCL), and positive control antigen-stimulated γδ T cells expressing Th1 (IFNγ, TNFα, IL-2) and Th17 (IL-17A, IL-17F, IL-22) cytokine as well as cytotoxic (perforin [PFN], granzyme [GZE B], granulysin [GNLSN]) and immune (GMCSF, PD-1, CD69) markers in LTB (DM, PDM, NDM) comorbidities by flow cytometry. In the unstimulated (UNS) condition, we did not observe any significant difference in the frequencies of γδ T cells expressing Th1 and Th17 cytokine, cytotoxic, and immune markers. In contrast, upon PPD antigen stimulation, the frequencies of γδ T cells expressing Th1 (IFNγ, TNFα) and Th17 (IL-17F, IL-22) cytokine, cytotoxic (PFN, GZE B, GNLSN), and immune (CD69) markers were significantly diminished in LTB DM and/or PDM individuals compared to LTB NDM individuals. Similarly, upon WCL antigen stimulation, the frequencies of γδ T cells expressing Th1 (TNFα) and Th17 (IL-17A, IL-22) cytokine, cytotoxic (PFN), and immune (PD-1, CD69) markers were significantly diminished in LTB DM and/or PDM individuals compared to LTB NDM individuals. Finally, upon P/I stimulation we did not observe any significant difference in the γδ T cell frequencies expressing cytokine, cytotoxic, and immune markers between the study populations. The culture supernatant levels of IFNγ, TNFα, and IL-17A cytokines were significantly increased in LTB DM and PDM after stimulation with Mtb antigens compared to LTB NDM individuals. Therefore, diminished γδ T cells expressing cytokine, cytotoxic, and other immune markers and elevated levels of cytokines in the supernatants is a characteristic feature of LTB PDM/DM co-morbidities.
Highlights
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), affects around 10 million people and causes 1.4 million deaths worldwide in the year 2019 (World Health Organization, 2020)
We reveal that gd T cells expressing Th1, Th17, cytotoxic, and immune markers were significantly diminished in latent tuberculosis (LTB) diabetes mellitus (DM) and/or PDM compared to LTB NDM-coinfected individuals
The frequencies of gd T cells expressing Th1 cytokines were significantly reduced in purified protein derivative (PPD) [IFNg (geometric mean (GM) of DM is 0.568 versus Geometric means (GM) of PDM is 1.590 vs. GM of NDM is 1.510), TNFa (GM of DM is 0.402 vs. GM of PDM is 0.337 vs. GM of NDM is 0.906)] and WCL [TNFa (GM of DM is 0.439 vs. GM of PDM is 0.449 vs. GM of NDM is 0.913)] antigen stimulation in LTB DM and PDM individuals compared to LTB NDM individuals
Summary
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), affects around 10 million people and causes 1.4 million deaths worldwide in the year 2019 (World Health Organization, 2020). LTB DM is associated with decreased systemic and Mtb antigen-specific levels of type 1 and type 17 cytokines (Kumar et al, 2014). The previous study has shown that LTB PDM was characterized by decreased antigen-specific frequencies of T helper (Th)1/T cytotoxic (Tc) and Th17/Tc17 cells (Kumar et al, 2017). Antigen-specific gd T cells constitute a primary innate immune defense that could play an important function in anti-mycobacteria-mediated immunity. Our data suggest that diminished frequencies of gd T cells expressing cytokines and cytotoxic markers and elevated cytokines in the supernatants are an important characteristic feature in LTB DM and PDM comorbidities
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