HLA-E-restricted CD8+ T Lymphocytes Efficiently Control Mycobacterium tuberculosis and HIV-1 Coinfection

被引：15

作者：

La Manna, Marco Pio ^{[1
,2
]}

Orlando, Valentina ^{[1
,2
]}

Prezzemolo, Teresa ^{[1
,2
]}

Di Carlo, Paola ^{[3
]}

Cascio, Antonio ^{[3
]}

Delogu, Giovanni ^{[4
,5
]}

Poli, Guido ^{[6
,7
]}

Sullivan, Lucy C. ^{[8
]}

Brooks, Andrew G. ^{[8
]}

Dieli, Francesco ^{[1
,2
]}

Caccamo, Nadia ^{[1
,2
]}

机构：

[1] Univ Palermo, Cent Lab Adv Diag & Biomed Res, Via Vespro 129, I-90127 Palermo, Italy

[2] Univ Palermo, Dept Biomed Neurosci & Adv Diagnost, Palermo, Italy

[3] Univ Palermo, Dept Sci Hlth Promot & Mother Child Care G DAless, Palermo, Italy

[4] Univ Cattolica Sacro Cuore, Inst Microbiol, Rome, Italy

[5] Inst Sci Based Care & Res IRCCS Rome, Fdn Policlin Univ Gemelli, Rome, Italy

[6] Ist Sci San Raffaele, AIDS Immunopathogenesis Unit, Milan, Italy

[7] Univ Vita Salute San Raffaele, Sch Med, Milan, Italy

[8] Univ Melbourne, Dept Microbiol & Immunol, Peter Doherty Inst Infect & Immun, Melbourne, Vic, Australia

来源：

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY | 2020年 / 62卷 / 04期

基金：

欧盟地平线“2020”;

关键词：

CD8(+) T lymphocytes; HLA-E; Mycobacterium tuberculosis; HIV-1; tetramers; SELECTIVE DOWN-REGULATION; IMMUNODEFICIENCY-VIRUS; CELL SUBSETS; NEF ALLELES; INFECTION; MOLECULES; IMMUNITY;

D O I：

10.1165/rcmb.2019-0261OC

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 HLAE-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 c ytolytic 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.

引用

页码：430 / 439

页数：10