Activation-induced Cell Death Drives Profound Lung CD4(+) T-Cell Depletion in HIV-associated Chronic Obstructive Pulmonary Disease

作者：Popescu Lulia^*; Drummond M Bradley; Gama Lucio; Coon Tiffany; Merlo Christian A; Wise Robert A; Clements Janice E; Kirk Gregory D; McDyer John F

来源：American Journal of Respiratory and Critical Care Medicine, 2014, 190(7): 744-755.

DOI：10.1164/rccm.201407-1226OC

• HIV
• T cells
• COPD
• apoptosis
• immune activation

Rationale: As overall survival improves, individuals with HIV infection become susceptible to other chronic diseases, including accelerated chronic obstructive pulmonary disease (COPD).
Objectives: To determine whether individuals with HIV-associated COPD exhibit dysregulated lung mucosal T-cell immunity compared with control subjects.
Methods: Using flow cytometry, we evaluated peripheral blood and lung mucosal T-cell immunity in 14 HIV+COPD+, 13 HIV+COPD-, and 7 HIV-COPD+ individuals.
Measurements and Main Results: HIV+COPD+ individuals demonstrated profound CD4(+) T-cell depletion with reduced CD4/CD8 T-cell ratios in bronchoalveolar lavage-derived lung mononuclear cells, not observed in peripheral blood mononuclear cells, and diminished CD4(+) T cell absolute numbers, compared with control subjects. Furthermore, HIV+COPD+ individuals demonstrated decreased pulmonary HIV-specific and staphylococcal enterotoxin B-reactive CD4(+) memory responses, including loss of multifunctionality, compared with HIV+COPD- control subjects. In contrast, lung mucosal HIV-specific CD8(+) T-cell responses were preserved. Lung CD4(+) T cells from HIV+COPD+ individuals expressed increased surface Fas death receptor (CD95) and programmed death-1, but similar bronchoalveolar lavage viral loads as control subjects. However, programmed death-1 expression inversely correlated with HIV-specific lung CD4(+)IFN-gamma(+) T-cell responses, suggesting functional exhaustion. Moreover, lung CD4(+) T cells from HIV+COPD+ patients demonstrated increased basal and HIV antigen-induced expression of the early apoptosis marker annexin V compared with control subjects, which was significantly attenuated with anti-Fas blockade. Lastly, lung mucosal, but not blood, CD4(+)/CD8(+) ratios from HIV+ patients significantly correlated with the FEV1, but not in HIV-COPD+ patients.
Conclusions: Together, our results provide evidence for profound lung mucosal CD4(+) T-cell depletion via a Fas-dependent activation-induced cell death mechanism, along with impaired HIV-specific CD4(+) immunity as immunologic features of HIV-associated COPD.

• 出版日期2014-10-1