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Natural killer (NK) and invariant NKT (iNKT) cells are unique innate lymphocytes that coordinate diverse immune responses and display antimycobacterial potential. However, the role of NK and iNKT cells expressing cytokines, cytotoxic, and immune markers in latent tuberculosis (LTB), diabetes mellitus (DM), or preDM (PDM) and nonDM (NDM) comorbidities is not known. Thus, we have studied the unstimulated (UNS), Mycobacterium tuberculosis (Mtb [PPD, WCL]), and mitogen (P/I)-stimulated NK and iNKT cells expressing Type 1 (IFN γ , TNF α , and IL-2), Type 17 (IL-17A, IL-17F, and IL-22) cytokines, cytotoxic (perforin, granzyme B, and granulysin) and immune (GMCSF, PD-1, and CD69) markers in LTB comorbidities by dimensionality reduction and flow cytometry. Our results suggest that LTB DM and PDM individuals express diverse NK and iNKT cell immune clusters compared to LTB NDM individuals. In UNS condition, frequencies of NK and iNKT cells expressing markers are not significantly different. After Mtb antigen stimulation, NK cell expressing [Type 1 (IFN γ , TNF α , and IL-2), GMCSF in PPD and IFN γ in WCL), Type 17 [(IL-17A), PD-1 in PPD), (IL-17A, IL-17F, and IL-22), PD-1 in WCL], and cytotoxic (perforin, granzyme B in PPD, and WCL)] marker frequencies were significantly reduced in LTB DM and/or PDM individuals compared to LTB NDM individuals. Similarly, iNKT cells expressing [Type 1 (IFN γ , IL-2), GMCSF in PPD), TNF α , GMCSF in WCL), Type 17 (IL-17A), PD-1 in PPD, IL-17F in WCL) cytokines were increased and cytotoxic or immune (perforin, granzyme B, granulysin), CD69 in PPD, perforin and CD69 in WCL] marker frequencies were significantly diminished in LTB DM and/or PDM compared to LTB NDM individuals. Finally, NK and iNKT cell frequencies did not exhibit significant differences upon positive control antigen stimulation between the study population. Therefore, altered NK cell and iNKT cells expressing cytokines, cytotoxic, and immune markers are characteristic features in LTB PDM/DM comorbidities., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2022 Gokul Raj Kathamuthu et al.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kathamuthu, Kumar, Moideen, Menon and Babu.)

Background: Alterations in β common (βC) and γ common (γC) chain cytokines have been described in pulmonary tuberculosis. However, their role in tuberculous lymphadenitis (TBL) disease has not been assessed., Methods: Thus, in the present study, we have examined the systemic levels of βC and γC chain cytokines in TBL, latent tuberculosis (LTB) and healthy control (HC) individuals. We have examined the discriminatory potential of both family of cytokines using ROC analysis. Finally, we measured the pre and post-treatment responses of these cytokines after anti-tuberculosis treatment., Results: TBL individuals exhibit significantly increased (IL-3) and diminished systemic levels of (IL-5, GM-CSF) βC cytokines compared to LTB and HC individuals. TBL individuals also exhibit significantly diminished (IL-2, IL-7) and elevated (IL-4, IL-9) levels of γC cytokines compared to LTB and/or HC. ROC analysis shows a clear discriminatory capacity of both βC (IL-5) and γC (IL-2) chain cytokines to distinguish TBL from LTB and HCs. The systemic levels of βC chain cytokines were not significantly altered, but in contrast γC (IL-2 and IL-7) cytokines were significantly modulated after treatment. Finally, no significant correlation was observed for βC and γC chain cytokines with their respective lymphocyte count of TBL individuals., Conclusions: Hence, we conclude that altered plasma levels of βC and γC cytokines are the characteristics of immune alteration in TBL disease and certain cytokines were modulated after treatment., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Helminth infections are known to regulate cytokine responses in both pulmonary and latent tuberculosis infection. Whether helminth infections also modulate cytokine responses in extra-pulmonary tuberculosis, specifically tuberculous lymphadenitis (TBL), has not been examined thus far. Methodology: Hence, to determine the cytokine profile in helminth-TBL coinfection, we measured the systemic and mycobacterial (TB)–antigen stimulated levels of Type 1, Type 2, Type 17, regulatory and pro-inflammatory cytokines in TBL individuals coinfected with or without Strongyloides stercoralis (Ss) infection. Significant findings: TBL-Ss+ individuals have significantly higher bacterial burdens in the affected lymph nodes in comparison to TBL-Ss- individuals. TBL-Ss+ individuals exhibit significantly enhanced plasma levels of Type 2 (IL-5 and IL-13), Type 17 (IL-17 and IL-22) and regulatory (IL-10) cytokines in comparison to TBL-Ss- individuals. In contrast, TBL-Ss+ individuals exhibit significantly diminished plasma levels of pro-inflammatory cytokines (IL-1α and GM-CSF) in comparison to TBL-Ss- individuals. TBL-Ss+ individuals also exhibit significantly diminished unstimulated or mycobacterial—antigen stimulated levels of Type 1, Type 17 or IL-1 family cytokines in comparison to TBL-Ss- individuals but no differences in mitogen stimulated cytokine levels. Conclusion: Therefore, our data reveal a profound influence of Ss infection on the bacteriological profile of TBL and suggesting that the underlying modulation of cytokine responses might be a mechanism by which this helminth infection could impart a detrimental effect on the pathogenesis of TBL disease. Author summary: Strongyloides stercoralis (Ss) infects about 30–100 million people worldwide and it is the main causative agent of strongyloidiasis, a chronic parasitic infection. Similarly, tuberculosis (TB) affects nearly 2 billion people and both Ss and TB are co-endemic as well as share a major global disease burden. Earlier studies have revealed that helminth co-infection can modify the effect produced by the host immunity against Mycobacterium tuberculosis. However, no studies have examined the association of helminth co-infection with extra-pulmonary TB, especially in tuberculous lymphadenitis (TBL). In the present study, we have addressed this gap by measuring the cytokine profile in co-infected helminth-TBL individuals. Our study first shows that TBL-Ss+ co-infection is associated with "higher bacterial burden" in the affected lymph nodes. Our study also shows that co-infection is associated with alterations in plasma cytokines, specifically Type 2, regulatory and Type 17 cytokines were elevated and pro-inflammatory cytokines were reduced. Our study demonstrates significantly diminished unstimulated or TB—antigen stimulated levels of Type 1, Type 17 or IL-1 family of cytokines in TBL-Ss+ coinfected individuals. Hence, we conclude that helminth coinfection can possibly skew the protective immunity in TBL disease or infection. [ABSTRACT FROM AUTHOR]