title: Cytomegalovirus-specific responses of CD38⁺ memory T cells are skewed towards IFN-γ and dissociated from CD154 in HIV-1 infection.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Olvera-García
authors.forename: Enrique
authors.initials: E
authors.lastname: Espinosa
authors.forename: Scott F
authors.initials: SF
authors.lastname: Sieg
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lederman
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis*; D023201:CD40 Ligand / Q000032:analysis*; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology*; D004768:Enterotoxins / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D007376:Interleukin-2 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D004768:Enterotoxins; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; C031818:enterotoxin B, staphylococcal; D007371:Interferon-gamma; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1