title: Hyperexpansion of Functional Viral-Specific CD8+ T Cells in Lymphopenia-Associated MCMV Pneumonitis.
abstract: Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in immunocompromised hosts, many of whom undergo significant periods of lymphopenia. However, the impact of lymphopenia and subsequent immune reconstitution on T cell responses and pulmonary pathology are poorly understood. Using a model of primary murine CMV infection in mice treated with cyclophosphamide (CY), the relationship of CD8+ T cell reconstitution to pneumonitis pathology was studied. Female BALB/c mice were infected with murine CMV (MCMV) with/without CY on day 1 post-infection. Lung pathology and viral specific T cell responses were assessed on days 7-28. T cell lymphocyte subsets, effector responses, and MCMV specificity were assessed at baseline and after in vitro stimulation of cells with immediate-early peptide pp89. CY treatment of MCMV-infected mice resulted in interstitial pneumonitis not seen with MCMV alone. Compared to MCMV alone, on day 14, MCMV/CY mice had greater number of CD8+ T cells, a fourfold increase in absolute number of pp89 tetramer-specific CD8+ cells, and an eightfold increase in MCMV specific T cell effector responses (IFN-γ; p<0.001). This expansion was preceded by transient lymphopenia, increased viral titers, and, most strikingly, a 10-fold increased proliferative capacity in MCMV/CY mice. In the setting of CY-associated lymphopenia, concurrent MCMV infection alters immune reconstitution toward a hyperexpanded MCMV-specific CD8+ effector T cell pool that correlates with significant lung immunopathology.
authors.affiliation: 1Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Pali D
authors.initials: PD
authors.lastname: Shah
authors.affiliation: 1Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: 2Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Lendermon
authors.affiliation: 2Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Pipeling
authors.affiliation: 2Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: John F
authors.initials: JF
authors.lastname: McDyer
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003520:Cyclophosphamide; D005260:Female; D006566:Herpesviridae Infections / Q000276:immunology* / Q000821:virology; D017874:Immediate-Early Proteins / Q000276:immunology; D016867:Immunocompromised Host / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000276:immunology* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000276:immunology*; D011014:Pneumonia / Q000276:immunology / Q000821:virology; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D017874:Immediate-Early Proteins; C052612:cytomegalovirus immediate early phosphoprotein pp89; D007371:Interferon-gamma; D003520:Cyclophosphamide