Format

Send to

Choose Destination
Am J Respir Crit Care Med. 2014 Oct 1;190(7):744-55. doi: 10.1164/rccm.201407-1226OC.

Activation-induced cell death drives profound lung CD4(+) T-cell depletion in HIV-associated chronic obstructive pulmonary disease.

Author information

1
1 Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Abstract

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-γ(+) 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.

KEYWORDS:

COPD; HIV; T cells; apoptosis; immune activation

PMID:
25137293
PMCID:
PMC4299615
DOI:
10.1164/rccm.201407-1226OC
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center