Dataset Information

Invariant Natural Killer T-cell Dynamics in Human Immunodeficiency Virus-associated Tuberculosis.

ABSTRACT: BACKGROUND:Tuberculosis (TB) is the leading cause of mortality and morbidity in people living with human immunodeficiency virus (HIV) infection (PLWH). PLWH with TB disease are at risk of the paradoxical TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) when they commence antiretroviral therapy. However, the pathophysiology is incompletely understood and specific therapy is lacking. We investigated the hypothesis that invariant natural killer T (iNKT) cells contribute to innate immune dysfunction associated with TB-IRIS. METHODS:In a cross-sectional study of 101 PLWH and HIV-uninfected South African patients with active TB and controls, iNKT cells were enumerated using ?-galactosylceramide-loaded CD1d tetramers and subsequently functionally characterized by flow cytometry. In a second study of 49 people with HIV type 1 (HIV-1) and active TB commencing antiretroviral therapy, iNKT cells in TB-IRIS patients and non-IRIS controls were compared longitudinally. RESULTS:Circulating iNKT cells were reduced in HIV-1 infection, most significantly the CD4+ subset, which was inversely associated with HIV-1 viral load. iNKT cells in HIV-associated TB had increased surface CD107a expression, indicating cytotoxic degranulation. Relatively increased iNKT cell frequency in patients with HIV-1 infection and active TB was associated with development of TB-IRIS following antiretroviral therapy initiation. iNKT cells in TB-IRIS were CD4+CD8- subset depleted and degranulated around the time of TB-IRIS onset. CONCLUSIONS:Reduced iNKT cell CD4+ subsets as a result of HIV-1 infection may skew iNKT cell functionality toward cytotoxicity. Increased CD4- cytotoxic iNKT cells may contribute to immunopathology in TB-IRIS.

SUBMITTER: Walker NF

PROVIDER: S-EPMC7156773 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Invariant Natural Killer T-cell Dynamics in Human Immunodeficiency Virus-associated Tuberculosis.

Walker Naomi F NF Opondo Charles C Meintjes Graeme G Jhilmeet Nishtha N Friedland Jon S JS Elkington Paul T PT Wilkinson Robert J RJ Wilkinson Katalin A KA

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20200401 9

<h4>Background</h4>Tuberculosis (TB) is the leading cause of mortality and morbidity in people living with human immunodeficiency virus (HIV) infection (PLWH). PLWH with TB disease are at risk of the paradoxical TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) when they commence antiretroviral therapy. However, the pathophysiology is incompletely understood and specific therapy is lacking. We investigated the hypothesis that invariant natural killer T (iNKT) cells contribute t ...[more]

PMID: 31190065

Similar Datasets

Project description: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 (IFNγ, TNFα, 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 (IFNγ, TNFα, and IL-2), GMCSF in PPD and IFNγ 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 (IFNγ, IL-2), GMCSF in PPD), TNFα, 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.

Project description:BackgroundHuman CD1d-restricted, invariant natural killer T cells (iNKT) are a unique class of T lymphocytes that recognise glycolipid antigens such as alpha-galactosylceramide (alphaGalCer) and upon T cell receptor (TCR) activation produce both Th1 and Th2 cytokines. iNKT cells expand when cultured in-vitro with alphaGalCer and interleukin 2 (IL-2) in a CD1d-restricted manner. However, the expansion ratio of human iNKT cells varies between individuals and this has implications for attempts to manipulate this pathway therapeutically. We have studied a panel of twenty five healthy human donors to assess the variability in their in-vitro iNKT cell expansion responses to stimulation with CD1d ligands and investigated some of the factors that may influence this phenomenon.ResultsAlthough all donors had comparable numbers of circulating iNKT cells their growth rates in-vitro over 14 days in response to a range of CD1d ligands and IL-2 were highly donor-dependent. Two reproducible donor response patterns of iNKT expansion were seen which we have called 'strong' or 'poor' iNKT responders. Donor response phenotype did not correlate with age, gender, frequency of circulating iNKT, or with the CD1d ligand utilised. Addition of exogenous recombinant human interleukin 4 (IL-4) to 'poor' responder donor cultures significantly increased their iNKT proliferative capacity, but not to levels equivalent to that of 'strong' responder donors. However in 'strong' responder donors, addition of IL-4 to their cultures did not significantly alter the frequency of iNKT cells in the expanded CD3+ population.Conclusion(i) in-vitro expansion of human iNKT cells in response to CD1d ligand activation is highly donor variable, (ii) two reproducible patterns of donor iNKT expansion were observed, which could be classified into 'strong' and 'poor' responder phenotypes, (iii) donor iNKT response phenotypes did not correlate with age, gender, frequency of circulating iNKT cells, or with the CD1d ligand utilised, (iv) addition of IL-4 to 'poor' but not 'strong' responder donor cultures significantly increased their in-vitro iNKT cell expansion to alphaGalCer.

Dataset Information

Invariant Natural Killer T-cell Dynamics in Human Immunodeficiency Virus-associated Tuberculosis.

Publications

Invariant Natural Killer T-cell Dynamics in Human Immunodeficiency Virus-associated Tuberculosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets