title: IL-12-Dependent Cytomegalovirus-Specific CD4+ T Cell Proliferation, T-bet Induction, and Effector Multifunction during Primary Infection Are Key Determinants for Early Immune Control.
abstract: CMV remains an important opportunistic pathogen in solid organ and hematopoietic cell transplantation, particularly in lung transplant recipients (LTRs). LTRs mismatched for CMV (donor(+)/recipient(-); D(+)R(-)) are at high risk for active CMV infection and increased mortality; however, the immune correlates of viral control remain incompletely understood. We prospectively studied 27 D(+)R(-) LTRs during primary CMV infection to determine whether acute CD4(+) T cell parameters differentiated the capacity for viral control during early chronic infection. Unexpectedly, the T-box transcription factor, T-bet, was expressed at low levels in CD4(+) compared with CD8(+) T cells during acute primary infection. However, the capacity for in vitro CMV phosphoprotein 65-specific proliferation and CD4(+)T-bet(+) induction differentiated LTR controllers from early viremic relapsers, correlating with granzyme B loading and effector multifunction. Furthermore, impaired CMV-specific proliferative responses from relapsers, along with T-bet, and effector function could be significantly rescued, most effectively with phosphoprotein 65 Ag and combined exogenous IL-2 and IL-12. Acute CD4(+) T cell CMV-specific proliferative and effector responses were highly IL-12-dependent in blocking studies. In addition, we generated monocyte-derived dendritic cells using PBMC obtained during primary infection from relapsers and observed impaired monocyte-derived dendritic cell differentiation, a reduced capacity for IL-12 production, but increased IL-10 production compared with controls, suggesting an APC defect during acute CMV viremia. Taken together, these data show an important role for CMV-specific CD4(+) effector responses in differentiating the capacity of high-risk LTRs to establish durable immune control during early chronic infection and provide evidence for IL-12 as a key factor driving these responses.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
authors.forename: Iulia
authors.identifier: http://orcid.org/0000-0003-4294-1223
authors.initials: I
authors.lastname: Popescu
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Pipeling
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
authors.forename: Hannah
authors.identifier: http://orcid.org/0000-0003-3354-7646
authors.initials: H
authors.lastname: Mannem
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and.
authors.forename: Pali D
authors.initials: PD
authors.lastname: Shah
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Orens
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Stephen A
authors.identifier: http://orcid.org/0000-0002-6062-8022
authors.initials: SA
authors.lastname: Migueles
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; mcdyerjf@upmc.edu.
authors.forename: John F
authors.initials: JF
authors.lastname: McDyer
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018664:Interleukin-12; D016040:Lung Transplantation / Q000009:adverse effects*; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020825:T-Box Domain Proteins / Q000096:biosynthesis* / Q000276:immunology; D055815:Young Adult; D000098815:T-bet Transcription Factor
chemical_list: D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12