Effect of HIV infection on the function of CD8+ polycytotoxic T lymphocytes in human tuberculosis
Immunology
Parasitology and Biology of Tropical Infectious Disease Pathogens
Final Report Abstract
Tuberculosis is a major global burden with more than 10 million cases per year and 1.2 million fatalities, mostly children. Treatment of tuberculosis is problematic due to the long duration (at least 6 months), the necessity of combining four drugs with potential side effects and the emergence of drug-resistant strains. In addition, Mycobacterium tuberculosis (Mtb), the causative bacterium of tuberculosis, is an intracellular pathogen and antimicrobial drugs need to penetrate through membrane of macrophages. Therefore, novel therapeutic strategies to improve the outcome of treatment are desperately needed. One approach is to strengthen components of the human immune system by host-directed therapies. T-lymphocytes are a rational target for host-directed therapies, since they are critical for the activation of macrophages to eliminate the intracellular mycobacteria. Besides CD4+ T-lymphocytes that produce macrophage-activating cytokines, CD8+ T-lymphocytes contribute to the control of tuberculosis infection by lysing Mtb-infected macrophages and directly killing the intracellular pathogen. We recently showed that three molecules located in the granules of CD8+ CTL- namely granzyme B, perforin and granulysin- act in concert to perform these functions. CD8+ T-lymphocytes co-expressing these three molecules are termed polycytotoxic T-cells (P-CTL) (1). Here we investigated the frequency of P-CTL in the peripheral blood and the lung, the major site of tuberculosis infection. Since patients living with the human immune deficiency virus (HIV) are at high risk of developing tuberculosis, we investigated whether HIV-infection affects the frequency of P-CTL in the lung and the alveoli and may possibly explain the high susceptibility for tuberculosis. We found that CD8+ P-CTL can be enriched in the peripheral blood by selecting for Natural killer cell receptors NKG2A and NKG2C (2). Peripheral blood cells enriched for P-CTL showed increased antimicrobial activity against the intracellular Mtb as compared to T-cell subsets that do not express cytotoxic effector molecules (3). In the lung, which is the primary site of tuberculosis infection, P-CTL were readily detected in healthy individuals. Peripheral blood cells enriched for P-CTL by the expression of NK cell receptors in the alveolar space were predominantly CD8+. The frequency of P-CTL was decreased in the lung of patients with active tuberculosis as compared to Mtb-naïve individuals or donors with latent tuberculosis infection. The frequency of P-CTL was significantly lower in the peripheral blood of patients living with HIV as compared to HIV-negative individuals. In addition, the frequency of Mtb-specific P-CTL was higher in the peripheral blood than in bronchoalveolar lavage. Finally, the frequency of Mtb-specific P-CTL in the peripheral blood was lower in patients living with HIV and patients with active tuberculosis as compared donors with latent tuberculosis infection. These results suggest that P-CTL contribute to systemic and local protection in human tuberculosis and HIV infection by exerting antimicrobial activity. Therefore P-CTL may be an attractive target for host-directed therapies, especially in HIV- patients where the frequency and function of this subset is reduced.
Publications
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Polycytotoxic T lymphocytes in human Mycobacterium tuberculosis infection. Poster presentation at the LSTM Postgraduate Research conference; online, 21st to 22nd June 2022
Aaron P. Chirambo, David Mhango, Christine Mandalasi, Elizabeth Chimbayo, Cheusisime Kajanga, Steven Mitini-Nkhoma, Anstead Kankwatira, Rose Malamba, David Mzinza, Marc Zumwinkel, Kondwani Jambo, Steffen Stenger & Henry Mwandumba
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‘Polycytotoxic T lymphocytes in human Mycobacterium tuberculosis infection’. Oral presentation at the 11th Infectious Diseases in Africa symposium; Cape Town, South Africa, 5th to 10th September 2022
Aaron P. Chirambo, David Mhango, Christine Mandalasi, Elizabeth Chimbayo, Cheusisime Kajanga, Steven Mitini-Nkhoma, Anstead Kankwatira, Rose Malamba, David Mzinza, Marc Zumwinkel, Kondwani Jambo, Steffen Stenger & Henry Mwandumba
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“Effect of HIV infection on the function of CD8+ polycytotoxic T lymphocytes in human tuberculosis“, Spring Meeting 2022, International Graduate School in Molecular Medicine Ulm, Ulm University, 13.04.2022
Marc Zumwinkel
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“Functional characterization of polycytotoxic T lymphocytes in human tuberculosis”, Spring Meeting 2023 der International Graduate School in Molecular Medicine Ulm, Ulm University, 23.03.2022
Marc Zumwinkel, Markus Zähnle & Steffen Stenger
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Frequency and functional characterization of polycytotoxic T cells in human tuberculosis. International Graduate School in Molecular Medicine Ulm, Ulm University, 12.12.2023
Marc Zumwinkel
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Functional characterization of polycytotoxic T cells in human tuberculosis. beim Spring Meeting 2023 der International Graduate School in Molecular Medicine Ulm, Ulm University, 23.03.2023
Marc Zumwinkel
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The frequency of polycytotoxic T cells predict the antimicrobial activity of human lymphocytes against intracellular Mycobacterium tuberculosis. Joint Conference of the Société Française d’Immunologie (SFI) and the Deutsche Gesellschaft für Immunologie (DGfI): Abstracts. Location Strasbourg, France. Date September 26-29, 2023. Eur. J. Immunol. 2023.53, S2, page number(s):369. Meeting Abstract number: P 387
Marc Zumwinkel, M. Zaehnle, A. Chirambo, H. Mwandumba & S. Stenger
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The impact of HIV infection on human Mycobacterium tuberculosis specific polycytotoxic T lymphocytes. Poster presentation at the 2023 International Union of Immunological Societies conference; Cape Town, South Africa, 27th November to 3rd December 2023
Aaron P. Chirambo, David Mhango, Christine Mandalasi, Elizabeth Chimbayo, Cheusisime Kajanga, Steven Mitini-Nkhoma, Anstead Kankwatira, Rose Malamba, David Mzinza, Marc Zumwinkel, Kondwani Jambo, Steffen Stenger & Henry Mwandumba
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‘The impact of HIV infection on human Mycobacterium tuberculosis specific polycytotoxic T lymphocytes’. Oral presentation at the 2023 LSTM Postgraduate Research conference; online, 27th to 28th June 2023
Aaron P. Chirambo, David Mhango, Christine Mandalasi, Elizabeth Chimbayo, Cheusisime Kajanga, Steven Mitini-Nkhoma, Anstead Kankwatira, Rose Malamba, David Mzinza, Marc Zumwinkel, Kondwani Jambo, Steffen Stenger & Henry Mwandumba
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“The frequency of P-CTLs predict the antimicrobial activity of human lymphocytes against intracellular Mycobacterium tuberculosis”, Joint Conference of the Société Française d’Immunologie (SFI) and the Deutsche Gesellschaft für Immunologie (DGfI), Strasbourg, France, 26. – 29.09. 2023
Marc Zumwinkel, Markus Zähnle, Aaron Chirambo, Henry Mwandumba & Steffen Stenger
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„Effect of HIV infection on the function of CD8+ polycytotoxic T lymphocytes in human tuberculosis“, International Graduate School in Molecular Medicine Ulm, Ulm University, 02.07.2023
Marc Zumwinkel
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Polycytotoxic T cells mediate antimicrobial activity against intracellular Mycobacterium tuberculosis. Infection and Immunity, 93(1).
Zumwinkel, Marc; Chirambo, Aaron; Zähnle, Markus; Bürger, Max; Grieshober, Mark; Romahn, Vincent; Mwandumba, Henry & Stenger, Steffen
