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Circulating HIV-specific CD8+ cytotoxic T cells express CD38 and HLA-DR antigens
H N Ho1, L E Hultin, R T Mitsuyasu
1Department of Medicine, University of California, Los Angeles 90024-1745.
Insights
HIV infection elevates CD38 and HLA-DR on CD8+ cells. The study found that CD8+ cells expressing both CD38 and HLA-DR exhibit the highest HIV-specific cytotoxic T lymphocyte activity, though this marker combination isn't a reliable measure of function.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Elevated CD38 and HLA-DR (DR) expression is observed on CD8+ cells in individuals with HIV.
- The precise function of CD38 and its co-expression with DR on HIV-specific CD8+ cytotoxic T lymphocytes (CTL) in vivo remains unclear.
Purpose of the Study:
- To investigate the expression of CD38 and DR on circulating HIV-specific CD8+ CTL in HIV-seropositive subjects.
- To determine the correlation between the expression levels of these molecules and CTL activity against HIV antigens.
Main Methods:
- Purified CD8+ lymphocytes from HIV-seropositive subjects were assessed for CTL activity against HIV-infected targets.
- Three-color immunofluorescence sorting was used to isolate CD8+ cell subsets based on CD38 and DR expression.
- Flow cytometry was employed to enumerate lymphocyte populations.
Main Results:
- HIV-specific CD8+ CTL activity was detected against HIV gag, pol, and env proteins in a majority of subjects.
- The highest HIV-specific CTL activity was found in the highly purified DR+CD38+ CD8+ cell population.
- Elevated levels of DR+CD38+ CD8+ cells were observed in both asymptomatic HIV-seropositive individuals and AIDS patients compared to HIV-seronegative controls.
- However, the enumeration of DR+CD38+ CD8+ cells did not correlate with overall anti-HIV CTL activity.
Conclusions:
- This study provides the first evidence of CD38 expression on antigen-specific CD8+ CTL in vivo, confirming DR expression on these cells.
- While DR+CD38+ CD8+ cells display potent HIV-specific CTL activity, their enumeration is not a suitable surrogate marker for functional CTL responses.
- Reduced HIV-specific CTL activity, particularly against gag, correlated with lower CD4+ cell counts, suggesting a link to CD4+ T cell immunodeficiency in advanced HIV disease.
Abstract:
CD38, a molecule with multilineage distribution but unknown function, and the MHC class II molecule HLA-DR (DR) have markedly elevated levels of expression on CD8+ cells of HIV-infected people. This study investigated the expression of CD38 and DR Ag on circulating HIV-specific CD8+ CTL in HIV-seropositive subjects. Purified CD8+ lymphocytes from 22 participants in the University of California at Los Angeles Multicenter AIDS Cohort Study were screened for CTL activity against autologous EBV-immortalized lymphoblast targets infected with vaccinia vectors that carried HIVIIIB gag, pol, and env genes. Sixty-seven percent (14 of 21), 64% (14 of 22), and 9% (2 of 22), respectively, of the subjects had HIV-specific CD8+ CTL activity against gag, pol, and env proteins. CD8+ cells from 11 of the subjects who had high CTL activity were then FACS-separated using three-color immunofluorescence sorting. Circulating DR-CD38- CD8+ cells had little activity. Highly purified DR+CD38+ CD8+ cells had higher HIV-specific CTL activity than other CD8+ cells. DR+CD38- or DR-CD38+ CD8+ cells also mediated significant activity, but only about half as much on a per cell basis as DR+CD38+ CD8+ cells. This is the first report that the CD38 molecule is expressed in vivo on Ag-specific CD8+ CTL, and confirms previous reports that DR is expressed on these cells. Both asymptomatic HIV-seropositive subjects (144 +/- 132/mm3) and AIDS patients (253 +/- 178/mm3) had markedly elevated levels of DR+CD38+ CD8+ cells compared with the levels in HIV-seronegative controls (7 +/- 3/mm3). However, the level of anti-HIV CTL activity was not correlated with the level of DR+CD38+ CD8+ cells, indicating that enumeration of this lymphocyte population by flow cytometry most likely will not be a useful surrogate for measuring functional CTL activity. Low levels of HIV-specific CTL activity, especially against gag, were correlated with lower CD4+ cells numbers, suggesting that the loss of CD8+ T cell cytotoxic activity against HIV that has been reported to occur with advancing HIV disease progression may reflect in part the extent of CD4+ cell immunodeficiency in HIV-infected subjects.