Cytomegalovirus-specific responses of CD38⁺ memory T cells are skewed towards IFN-γ and dissociated from CD154 in HIV-1 infection.

OBJECTIVE: Despite the strong correlation of T-cell CD38 expression with HIV disease progression, evidence linking CD38 expression and dysfunction at the single cell level is scant. Since CD38⁺ memory CD4⁺ T cells, especially those from HIV-infected persons, fail to induce CD154 (CD40L) while responding to a superantigen with interferon (IFN)-γ or interleukin (IL)-2, we aimed to determine if recall responses to cytomegalovirus (CMV) were similarly affected in the CD38⁺ memory CD4⁺ T-cell subpopulation. DESIGN AND METHODS: Peripheral blood mononuclear cells from HIV+ patients and healthy controls were incubated 14 h with CMV antigens, the superantigen Staphylococcus aureus enterotoxin B or medium, and labeled for identification of central memory (T(CM)) and effector memory (T(EM)) CD4⁺ T cells, and for the intracellular detection of induced CD154, IFN-γ and/or IL-2 by flow cytometry.
RESULTS: Compared with CD38⁻ cells, CD38⁺ T(CM) cells from patients had less CD40L induction after CMV stimulation, and increased IFN-γ response. Patients' CD38⁺ T(EM) cells showed a lower IL-2 response, and tended to have a greater IFN-γ response, in which CD154 induction frequently failed. CMV-specific responses of patients' CD38⁺ T(CM) and T(EM) cells were dominated by IFN-γ, and almost all IL-2⁺ cells co-expressed IFN-γ. IL-2 responses to the polyclonal activator S. aureus enterotoxin B were also significantly less frequent among CD38⁺ T(CM) and T(EM) cells than in CD38⁻ cells.
CONCLUSION: Patients' CD38⁺ memory CD4⁺T-cell responses to CMV favor the effector cytokine IFN-γ over IL-2, in the context of deficient CD154 induction, which may limit co-stimulation, proliferation and survival.