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Background: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a clinical aggravation of TB symptoms observed among a fraction of HIV coinfected patients shortly after the start of antiretroviral therapy (ART). Of note, TB-IRIS is characterized by exacerbated inflammation and tissue damage that occurs in response to the elevated production of CD4+ T cell-derived IFN-γ. Nevertheless, the possible participation of CD8+ T cells in TB-IRIS development remains unclear. Methods: We performed a comprehensive assessment of the composition of CD8+ T cell memory subsets and their association with circulating inflammation-related molecules in TB-HIV coinfected patients initiating ART. Results: We found that TB-IRIS individuals display higher frequencies of Antigen-experienced CD8+ T cells during the onset of IRIS and that the levels of these cells positively correlate with baseline mycobacterial smear grade. TB-IRIS individuals exhibited higher frequencies of effector memory and lower percentages of naïve CD8+ T cells than their Non-IRIS counterparts. In both TB-IRIS and Non-IRIS patients, ART commencement was associated with fewer significant correlations among memory CD8+ T cells and cells from other immune compartments. Networks analysis revealed distinct patterns of correlation between each memory subset with inflammatory cytokines suggesting different dynamics of CD8+ T cell memory subsets reconstitution. TB-IRIS patients displayed lower levels of memory cells positive for CXCR3 (a chemokine receptor that plays a role in trafficking activated CD8+ T cells to the tissues) than Non-IRIS individuals before and after ART. Furthermore, we found that CXCR3+ naïve CD8+ T cells were inversely associated with the risk of TB-IRIS development. On the other hand, we noticed that the frequencies of CXCR3+ effector CD8+ T cells were positively associated with the probability of TB-IRIS development. Conclusion: Our data suggest that TB-IRIS individuals display a distinct profile of memory CD8+ T cell subsets reconstitution after ART initiation. Moreover, our data point to a differential association between the frequencies of CXCR3+ CD8+ T cells and the risk of TB-IRIS development. Collectively, our findings lend insights into the potential role of memory CD8+ T cells in TB-IRIS pathophysiology. [ABSTRACT FROM AUTHOR]

Genetic variations in chemokine genes influence the chemoattractive properties of T cells which may be associated with outcome of infections. In present study, we have investigated the regulatory role played by In1.1T/C (rs2280789) polymorphism of CCL5 and −135G/A (rs56061981) polymorphism of CXCL10 gene on intracellular CCL5 and CXCL10 expression in T cells. Whole blood cell cultures were stimulated with culture filtrate antigen (CFA) and infected with live M. tuberculosis were used for intracellular CCL5 and CXCL10 expression using flow cytometry. Genotyping was performed using polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP). Significantly higher expression of CCL5 expressing CD3+ and CD3+ CD8+ T cells were observed in HCs with In1.1TT genotype compared to C allele carrier (TT + TC) under unstimulated and CFA induced cultures (p < 0.05). In −135G/A (rs56061981) polymorphism, PTB patients with GG genotype showed a significantly decreased expression of CD3+ CXCL10+ and CD3+ CD4+ CXCL10+ T cells compared to A allele carrier (GA + AA) under unstimulated, CFA induced and M. tuberculosis infected cultures (P < 0.05). The present study suggest that TT genotype of CCL5 In1.1T/C (rs2280789) polymorphism play an important role to increased CCL5 expression in T cell which may enhanced Th1 immunity and help in protection against tuberculosis. The study also suggests GG genotype of CXCL10 −135G/A (rs56061981) polymorphism decreased CXCL10 expression in T cells which may have defective recruitment of mononuclear cells at the site of infection as well granuloma formation and in turn contribute to progression of TB. [ABSTRACT FROM AUTHOR]

Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an aberrant inflammatory response occurring in a subset of TB-HIV co-infected patients initiating anti-retroviral therapy (ART). Here, we examined monocyte activation by prospectively quantitating pro-inflammatory plasma markers and monocyte subsets in TB-HIV co-infected patients from a South Indian cohort at baseline and following ART initiation at the time of IRIS, or at equivalent time points in non-IRIS controls. Pro-inflammatory biomarkers of innate and myeloid cell activation were increased in plasma of IRIS patients pre-ART and at the time of IRIS; this association was confirmed in a second cohort in South Africa. Increased expression of these markers correlated with elevated antigen load as measured by higher sputum culture grade and shorter duration of anti-TB therapy. Phenotypic analysis revealed the frequency of CD14++CD16− monocytes was an independent predictor of TB-IRIS, and was closely associated with plasma levels of CRP, TNF, IL-6 and tissue factor during IRIS. In addition, production of inflammatory cytokines by monocytes was higher in IRIS patients compared to controls pre-ART. These data point to a major role of mycobacterial antigen load and myeloid cell hyperactivation in the pathogenesis of TB-IRIS, and implicate monocytes and monocyte-derived cytokines as potential targets for TB-IRIS prevention or treatment. [ABSTRACT FROM AUTHOR]

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a clinical aggravation of TB symptoms observed among a fraction of HIV coinfected patients shortly after the start of antiretroviral therapy (ART). Of note, TB-IRIS is characterized by exacerbated inflammation and tissue damage that occurs in response to the elevated production of CD4 + T cell-derived IFN-γ. Nevertheless, the possible participation of CD8 + T cells in TB-IRIS development remains unclear., Methods: We performed a comprehensive assessment of the composition of CD8 + T cell memory subsets and their association with circulating inflammation-related molecules in TB-HIV coinfected patients initiating ART., Results: We found that TB-IRIS individuals display higher frequencies of Antigen-experienced CD8 + T cells during the onset of IRIS and that the levels of these cells positively correlate with baseline mycobacterial smear grade. TB-IRIS individuals exhibited higher frequencies of effector memory and lower percentages of naïve CD8 + T cells than their Non-IRIS counterparts. In both TB-IRIS and Non-IRIS patients, ART commencement was associated with fewer significant correlations among memory CD8 + T cells and cells from other immune compartments. Networks analysis revealed distinct patterns of correlation between each memory subset with inflammatory cytokines suggesting different dynamics of CD8 + T cell memory subsets reconstitution. TB-IRIS patients displayed lower levels of memory cells positive for CXCR3 (a chemokine receptor that plays a role in trafficking activated CD8 + T cells to the tissues) than Non-IRIS individuals before and after ART. Furthermore, we found that CXCR3 + naïve CD8 + T cells were inversely associated with the risk of TB-IRIS development. On the other hand, we noticed that the frequencies of CXCR3 + effector CD8 + T cells were positively associated with the probability of TB-IRIS development., Conclusion: Our data suggest that TB-IRIS individuals display a distinct profile of memory CD8 + T cell subsets reconstitution after ART initiation. Moreover, our data point to a differential association between the frequencies of CXCR3 + CD8 + T cells and the risk of TB-IRIS development. Collectively, our findings lend insights into the potential role of memory CD8 + T cells in TB-IRIS pathophysiology., 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 © 2022 Tibúrcio, Narendran, Barreto-Duarte, Queiroz, Araújo-Pereira, Anbalagan, Nayak, Ravichandran, Subramani, Antonelli, Satagopan, Anbalagan, Porter, Sher, Swaminathan, Sereti and Andrade.)

Immune reconstitution inflammatory syndrome (IRIS) occurs in up to 40% of individuals co-infected with pulmonary tuberculosis (PTB) and HIV, primarily upon antiretroviral therapy (ART) initiation. Phenotypic changes in T-cells during TB-IRIS and their relationship with systemic inflammation are not fully understood. In this prospective cohort study, we followed 48 HIV-positive patients with PTB from South India before and after ART initiation, examining T-lymphocyte subsets and inflammatory biomarkers in peripheral blood. Quantification of naïve (CD27 + CD45RO - ) as well as effector memory CD4 + T cells (CD27 - CD45RO + ) at weeks 2-6 after ART initiation could distinguish TB-IRIS from non-IRIS individuals. Additional analyses revealed that ART reconstituted different quantities of CD4 + T lymphocyte subsets with preferential expansion of CXCR3 + CCR6 - cells in TB-IRIS patients. Moreover, there was an expansion and functional restoration of central memory (CD27 + CD45RO + ) CXCR3 + CCR6 - CD4 + lymphocytes and corresponding cytokines, with reduction in CXCR3 - CCR6 + cells after ART initiation only in those who developed TB-IRIS. Together, these observations trace a detailed picture of CD4 + T cell subsets tightly associated with IRIS, which may serve as targets for prophylactic and/or therapeutic interventions in the future.