HLA-E-restricted CD8(+) T Lymphocytes Efficiently Control Mycobacterium tuberculosis and HIV-1 Coinfection
AuthorLa Manna, MP; Orlando, V; Prezzemolo, T; Di Carlo, P; Cascio, A; Delogu, G; Poli, G; Sullivan, LC; Brooks, AG; Dieli, F; ...
Source TitleAmerican Journal of Respiratory Cell and Molecular Biology
PublisherAMER THORACIC SOC
AffiliationMicrobiology and Immunology
Document TypeJournal Article
CitationsLa Manna, M. P., Orlando, V., Prezzemolo, T., Di Carlo, P., Cascio, A., Delogu, G., Poli, G., Sullivan, L. C., Brooks, A. G., Dieli, F. & Caccamo, N. (2020). HLA-E-restricted CD8(+) T Lymphocytes Efficiently Control Mycobacterium tuberculosis and HIV-1 Coinfection. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 62 (4), pp.430-439. https://doi.org/10.1165/rcmb.2019-0261OC.
Access StatusAccess this item via the Open Access location
We investigated the contribution of human leukocyte antigen A2 (HLA-A2) and HLA-E-restricted CD8+ T cells in patients with Mycobacterium tuberculosis and human immunodeficiency virus 1 (HIV-1) coinfection. HIV-1 downregulates HLA-A, -B, and -C molecules in infected cells, thus influencing recognition by HLA class I-restricted CD8+ T cells but not by HLA-E-restricted CD8+ T cells, owing to the inability of the virus to downmodulate their expression. Therefore, antigen-specific HLA-E-restricted CD8+ T cells could play a protective role in Mycobacterium tuberculosis and HIV-1 coinfection. HLA-E- and HLA-A2-restricted Mycobacterium tuberculosis-specific CD8+ T cells were tested in vitro for cytotoxic and microbicidal activities, and their frequencies and phenotypes were evaluated ex vivo in patients with active tuberculosis and concomitant HIV-1 infection. HIV-1 and Mycobacterium tuberculosis coinfection caused downmodulation of HLA-A2 expression in human monocyte-derived macrophages associated with resistance to lysis by HLA-A2-restricted CD8+ T cells and failure to restrict the growth of intracellular Mycobacterium tuberculosis. Conversely, HLA-E surface expression and HLA-E-restricted cytolytic and microbicidal CD8 responses were not affected. HLA-E-restricted and Mycobacterium tuberculosis-specific CD8+ T cells were expanded in the circulation of patients with Mycobacterium tuberculosis/HIV-1 coinfection, as measured by tetramer staining, but displayed a terminally differentiated and exhausted phenotype that was rescued in vitro by anti-PD-1 (programmed cell death protein 1) monoclonal antibody. Together, these results indicate that HLA-E-restricted and Mycobacterium tuberculosis-specific CD8+ T cells in patients with Mycobacterium tuberculosis/HIV-1 coinfection have an exhausted phenotype and fail to expand in vitro in response to antigen stimulation, which can be restored by blocking the PD-1 pathway using the specific monoclonal antibody nivolumab.
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