Background
HIV-specific CD8 T cells can control HIV replication but become increasingly exhausted and dysfunctional with progressing disease. It has been previously shown that this is caused by a lack of CD4 T cell help in addition to persistent antigenemia. However, the interplay between T cells and their functions and the role of protein specificity in the crosstalk between CD4 and CD8 T subsets during chronic HIV infection has not been investigated.
Methods
To determine the function of HIV-specific CD4 and CD8 T cell responses targeting different proteins we collected peripheral blood samples of 27 untreated individuals with HIV. Isolated peripheral blood mononuclear cells were labeled with fluorescently tagged HLA-peptide tetramers presenting immunodominant epitopes of the HIV proteome (Figure 1) and stimulated with soluble peptides. The expression of surface proteins and cytokines in response to peptide stimulation was monitored by flow cytometry.
Results
We observed comparable frequencies of cells recognizing immunodominant epitopes of the HIV proteome among the CD4 and CD8 T subsets. Their functional profiles, however, differed significantly even when targeting the same protein with CD4 T cells being less responsive to stimulation (p<0.0001) and expressing high levels of CXCR5 (p<0.001), CD40L (p<0.05), and IL-4/-13 (p<0.0001) while CD8 T cells expressed higher levels of PD-1 (p<0.001), CD107a (p<0.0001), IFN-γ (p<0.0001) and IL-2 (p<0.001). Intriguingly, protein specificity played an important role in the case of CD4 T cells where cells targeting epitopes within the p24 protein showed increased PD-1 expression (p<0.01), cytotoxicity (p<0.001), and responsiveness to stimulation (p<0.01) while cells specific for the gp120 showed increased CXCR5 (p<0.0001) expression. In comparison to CD8 T cells, more CD4 T cell functions were associated with viral load and IFN-γ-expression was inversely correlated with the viral load for both subsets (r=-0.49, p<0.001 for CD4 and r=-0.54, p<0.01 for CD8 T cells). No dependence on the protein specificity was observed when correlating different functions of the tetramer-specific CD4 and CD8 T cells.
Conclusions
Taken together our findings demonstrate distinct functional profiles of CD4 and CD8 T cells targeting the same HIV protein and stronger dependence of CD4 T cells on viremia and protein specificity. The interplay between the CD4 and CD8 T cells was not dependent on protein co-targeting.
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