Robust Reconstitution of Tuberculosis-Specific Polyfunctional CD4<sup>+</sup>T-Cell Responses and Rising Systemic Interleukin 6 in Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

Ravimohan, Shruthi; Tamuhla, Neo; Nfanyana, Kebatshabile; Steenhoff, Andrew P.; Letlhogile, Rona; Frank, Ian; MacGregor, Rob Roy; Gross, Robert; Weissman, Drew; Bisson, Gregory P.

doi:10.1093/cid/civ978

Cited by 43 publications

(40 citation statements)

References 38 publications

(85 reference statements)

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“…Correspondingly, IL-6 neutralization increases IFN-γ-mediated killing of intracellular Mtb by inducing autophagy [28]. In human TB patients, IL-6 is implicated in the pathogenesis of the immune reconstitution inflammatory syndrome [29,30]…”

Section: Discussionmentioning

confidence: 99%

NK-CD11c+ Cell Crosstalk in Diabetes Enhances IL-6-Mediated Inflammation during Mycobacterium tuberculosis Infection

et al. 2016

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In this study, we developed a mouse model of type 2 diabetes mellitus (T2DM) using streptozotocin and nicotinamide and identified factors that increase susceptibility of T2DM mice to infection by Mycobacterium tuberculosis (Mtb). All Mtb-infected T2DM mice and 40% of uninfected T2DM mice died within 10 months, whereas all control mice survived. In Mtb-infected mice, T2DM increased the bacterial burden and pro- and anti-inflammatory cytokine and chemokine production in the lungs relative to those in uninfected T2DM mice and infected control mice. Levels of IL-6 also increased. Anti-IL-6 monoclonal antibody treatment of Mtb-infected acute- and chronic-T2DM mice increased survival (to 100%) and reduced pro- and anti-inflammatory cytokine expression. CD11c+ cells were the major source of IL-6 in Mtb-infected T2DM mice. Pulmonary natural killer (NK) cells in Mtb-infected T2DM mice further increased IL-6 production by autologous CD11c+ cells through their activating receptors. Anti-NK1.1 antibody treatment of Mtb-infected acute-T2DM mice increased survival and reduced pro- and anti-inflammatory cytokine expression. Furthermore, IL-6 increased inflammatory cytokine production by T lymphocytes in pulmonary tuberculosis patients with T2DM. Overall, the results suggest that NK-CD11c+ cell interactions increase IL-6 production, which in turn drives the pathological immune response and mortality associated with Mtb infection in diabetic mice.

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Section: Discussionmentioning

confidence: 99%

NK-CD11c+ Cell Crosstalk in Diabetes Enhances IL-6-Mediated Inflammation during Mycobacterium tuberculosis Infection

et al. 2016

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“…Several studies illustrated that a protective T cell response has signatures that feature highly polyfunctional HCV-specific CD8 ϩ T cells, which contribute to the substantial breadth and height of magnitude of responses to multiple viral determinants, in particular, the viral nonstructural (NS) proteins (16,17). The impact of polyfunctional T cells on protective immunity is not restricted to HCV but is commonly shared by diseases caused by other infectious pathogens, such as HIV, yellow fever virus, Ebola virus, cytomegaloviruses, and mycobacteria, as well as by cancer (18,19). However, in spite of its significance, the transcriptional mechanisms underlying antigen-specific T cell polyfunctionality are not completed understood.…”

mentioning

confidence: 99%

Hepatitis C Virus-Specific T Cell Receptor mRNA-Engineered Human T Cells: Impact of Antigen Specificity on Functional Properties

Balasiddaiah

Davanian

Aleman

et al. 2017

J Virol

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Therapy with genetically modified autologous T cells has shown great promise in cancer therapy. For an efficient control of hepatitis C virus (HCV) infection, cytotoxic T cells (CTL) are pivotal, but persistence of activated T cells may lead to liver toxicity. Here, anti-HCV T cell receptors (TCRs) recognizing the HCV nonstructural (NS) NS3 or NS5 viral peptide target were examined by mRNA transfection of human peripheral blood lymphocytes (PBLs) derived from healthy donors as well as chronically infected HCV patients. Immunological analysis shows that while the CTLs expressing the NS5-specific TCR reduced HCV RNA replication by a noncytotoxic mechanism, the NS3-specific TCR-redirected CTLs were polyfunctional and inhibited HCV RNA replication through antigen-specific cytotoxicity. Transcriptome signatures from these two types of CTL responses revealed uniquely expressed gene clusters upon encountering hepatoma target cells presenting endogenously expressed HCV proteins. The NS3 TCR induced a rapid expression of apoptotic signaling pathways and formation of embryonic gene clusters, whereas the NS5A TCR activation induced extended proliferative and metabolic pathways as the HCV target cells survived. Our results provide detailed insights into basic HCV T cell immunology and have clinical relevance for redirecting T cells to target virally infected hepatoma cells.IMPORTANCE Due to the protective ability of HCV-specific T cells and the hepatotoxic potential that they possess, there is a great need for the understanding of the functional aspects of HCV-specific T cells. To circumvent the low level of precursor frequency in patients, we engineered primary CD8 ϩ T cells by mRNA TCR vectors to confer HCV specificity to new T cells. HCV TCRs that differ in antigen specificity and polyfunctionality were examined. mRNA TCR engineering of peripheral blood lymphocytes from healthy donors or chronically infected HCV patients resulted in strikingly high levels of HCV TCR expression and HCV-specific responses. While a cytotoxicity response from a polyfunctional T cell activation caused hepatotoxicity and the rapid induction of apoptotic signaling pathways, the noncytotoxic T cell activation showed extended proliferative, metabolic pathways and persistence of HCV target cells. Our results provide detailed insights into basic HCV T cell immunology and have clinical relevance for immune protection of HCV-associated diseases.

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“…In this connection, TB-IRIS patients had significantly greater early increases in the frequency of tuberculosis-specific polyfunctional IFN-γ(+)/IL-2(+)/TNF-α(+) CD4 + T-cells on HAART. 34 Interestingly, Cryptococcus spp. was less frequent and was identified only in Spanish patients.…”

Section: Discussionmentioning

confidence: 99%

Immune Reconstitution Inflammatory Syndrome in HIV-Infected Immigrants

Pérez-Rueda

Hernández-Cabrera

Francés-Urmeneta

et al. 2017

The American Journal of Tropical Medicine and Hygiene

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Immune reconstitution inflammatory syndrome (IRIS) includes a group of potentially serious inflammatory processes that may be present in HIV-infected patients after initiating highly active antiretroviral therapy (HAART). is a worsening of symptoms, after an overwhelming response to a previously diagnosed opportunistic infection (OI); reveals a previously occult OI. The main objective of the study was to describe the epidemiological, clinical, and outcome data of HIV-infected immigrants, stratified according to high- or low-income countries of origin, who developed IRIS and to compare them with native-born Spanish patients. This retrospective study reviewed all patients with HIV infection admitted to the Unit of Infectious Diseases and Tropical Medicine between 1998 and 2014. IRIS was identified in 25/138 (18%) immigrant patients and 24/473 (5%) native-born Spanish patients infected with HIV. Most cases, 19/25 (76%), were of unmasking IRIS. The time elapsed between initiation of HAART and development of IRIS was significantly longer in patients with unmasking versus paradoxical IRIS. OIs, in particular due to mycobacteria, were the most frequently involved processes. Twenty percent of patients died. The comparison of immigrant and native-born patients found significant differences for both IRIS type (higher incidence of paradoxical forms among immigrants) and for the absence of malignancies in native-born patients. No significant differences were found when the data of immigrants from low- and high-income countries were compared.

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Robust Reconstitution of Tuberculosis-Specific Polyfunctional CD4⁺T-Cell Responses and Rising Systemic Interleukin 6 in Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

Cited by 43 publications

References 38 publications

NK-CD11c+ Cell Crosstalk in Diabetes Enhances IL-6-Mediated Inflammation during Mycobacterium tuberculosis Infection

NK-CD11c+ Cell Crosstalk in Diabetes Enhances IL-6-Mediated Inflammation during Mycobacterium tuberculosis Infection

Hepatitis C Virus-Specific T Cell Receptor mRNA-Engineered Human T Cells: Impact of Antigen Specificity on Functional Properties

Immune Reconstitution Inflammatory Syndrome in HIV-Infected Immigrants

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Robust Reconstitution of Tuberculosis-Specific Polyfunctional CD4+T-Cell Responses and Rising Systemic Interleukin 6 in Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

Cited by 43 publications

References 38 publications

NK-CD11c+ Cell Crosstalk in Diabetes Enhances IL-6-Mediated Inflammation during Mycobacterium tuberculosis Infection

NK-CD11c+ Cell Crosstalk in Diabetes Enhances IL-6-Mediated Inflammation during Mycobacterium tuberculosis Infection

Hepatitis C Virus-Specific T Cell Receptor mRNA-Engineered Human T Cells: Impact of Antigen Specificity on Functional Properties

Immune Reconstitution Inflammatory Syndrome in HIV-Infected Immigrants

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Robust Reconstitution of Tuberculosis-Specific Polyfunctional CD4⁺T-Cell Responses and Rising Systemic Interleukin 6 in Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome