title: T-bet:Eomes balance, effector function, and proliferation of cytomegalovirus-specific CD8+ T cells during primary infection differentiates the capacity for durable immune control.
abstract: CMV remains an important opportunistic pathogen in solid organ 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 23 D+R- LTRs during primary CMV infection to determine whether acute CD8(+) T cell parameters differentiated the capacity for viral control in early chronic infection. T-box transcription factors expression patterns of T-bet > Eomesodermin (Eomes) differentiated LTR controllers from viremic relapsers and reciprocally correlated with granzyme B loading, and CMV phosphoprotein 65 (pp65)-specific CD8(+)IFN-γ(+) and CD107a(+) frequencies. LTR relapsers demonstrated reduced CD8(+)Ki67(+) cells ex vivo and substantially impaired CD8(+)pp65-specific in vitro proliferative responses at 6 d, with concomitantly lower pp65-specific CD4(+)IL-2(+) frequencies, as compared with LTR controllers. However, CMV-specific in vitro proliferative responses could be significantly rescued, most effectively with pp65 Ag and exogenous IL-2, resulting in an increased T-bet:Eomes balance, and enhanced effector function. Using class I CMV tetramers, we observed similar frequencies between relapsers and controllers, although reduced T-bet:Eomes balance in tetramer(+) cells from relapsers, along with impaired CD8(+) effector responses to tetramer-peptide restimulation. Taken together, these data show impaired CMV-specific CD8(+) effector responses is not for complete lack of CMV-specific cells but rather underscores the importance of the T-bet:Eomes balance, with CMV-specific proliferation a key factor driving early T-bet expression and effector function in CD8(+) T cells during primary infection and differentiating the capacity of high-risk LTRs to establish immune control during early chronic infection.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Iulia
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, Pennsylvania.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Pipeling
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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, Maryland.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Orens
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: John F
authors.initials: JF
authors.lastname: McDyer
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002908:Chronic Disease; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000517:prevention & control; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000276:immunology; D011183:Postoperative Complications / Q000276:immunology* / Q000517:prevention & control; D011446:Prospective Studies; D012008:Recurrence; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000276:immunology; D055815:Young Adult; D000098815:T-bet Transcription Factor
chemical_list: C491199:EOMES protein, human; D007376:Interleukin-2; D010750:Phosphoproteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D007371:Interferon-gamma