Impaired CMV-specific CD4+ T cell responses in HIV patients responding to ART may reflect reductions in the proportions of pDC rather than changes in regulatory cytokines
Objectives: We have examined blood antigen presenting cell (APC) subpopulations and T cell interferon (IFN)-g responses to cytomegalovirus (CMV) in HIV patients responding to ART to determine if abnormalities of APC may be a cause of the CD4+ effector memory T cell (Tem) dysfunction that persists in some patients.
Methods: Study groups comprised 18 HIV patients with nadir CD4+ T cell counts <50 cells/ml, at least three years on ART and plasma HIV RNA <50 copies/mL for at least two years, and 10 HIV-negative controls. Responses to a crude CMV antigen measured by IFN-g ELISpot were shown to arise from CD4+ T cells. Myeloid dendritic cells (mDC; BDCA-1+), plasmacytoid dendritic cells (pDC; BDCA-4+), CD16+ dendritic cells (CD16+ DC; MDC-8+) and monocytes (CD14+) were enumerated by flow cytometry. Expression of IFN-a, IL-12, IL-23, IL-15, IL-18 and IL-10 mRNA in each unstimulated APC population was quantitated after purification using magnetic beads.
Results: HIV patients were divided into two groups based on IFN-g responses to CMV. Low responders produced fewer CMV IFN-g spots than high responders (p<0.0001) or controls (p=0.0003). Proportions of pDC were lower in low responders compared to high responders or controls (p=0.043 and p=0.034, respectively), but proportions of mDC were elevated (p=0.043 and p=0.002, respectively). Quantitation of cytokine mRNA revealed few differences between low and high responders. However compared with low responders, IL-15 mRNA levels were elevated in mDC from high responders (p=0.015) and IL-10 mRNA levels were elevated in CD16+ DC from low responders (p=0.036).
Conclusions: Impaired CMV-specific CD4+ T cell responses may reflect a reduced proportion and/or increased activation of pDC rather than changes in regulatory cytokines. Consequently, the recovery of pDC may predict restoration of antigen-specific T cell responses. Roles for IL-15 in survival of CD4+ Tem-cells and IL-10 in suppressing T cell IFN-g production warrant further investigation.
4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
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Impaired CMV-specific CD4+ T cell responses in HIV patients responding to ART may reflect reductions in the proportions of pDC rather than changes in regulatory cytokines.
4th IAS Conference on HIV Pathogenesis, Treatment and Prevention: