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

Olvera-García, Gustavoa; Espinosa, Enriquea; Sieg, Scott F.b; Lederman, Michael M.b

doi: 10.1097/QAD.0000000000000162
Basic Science: Concise Communications

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 (TCM) and effector memory (TEM) 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+ TCM cells from patients had less CD40L induction after CMV stimulation, and increased IFN-γ response. Patients’ CD38+ TEM 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+ TCM and TEM 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+ TCM and TEM 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.

Supplemental Digital Content is available in the text

aDepartment of Research in Immunology, National Institute for Respiratory Diseases (INER), Mexico

bDepartment of Medicine, Division of Infectious Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Correspondence to Michael M. Lederman, Department of Medicine, Case Western Reserve University, School of Medicine, 2061 Cornell Road, Cleveland, OH 44106, USA. E-mail:

Received 23 September, 2013

Revised 20 November, 2013

Accepted 20 November, 2013

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© 2014 Lippincott Williams & Wilkins, Inc.