Hyperexpansion of Functional Viral-Specific CD8+ T Cells in Lymphopenia-Associated MCMV Pneumonitis

• Published in: Viral immunology Vol. 28; no. 5; pp. 255 - 264
• Main Authors: Shah, Pali D., Zhong, Qiong, Lendermon, Elizabeth A., Pipeling, Matthew R., McDyer, John F.
• Format: Journal Article
• Language: English
• Published: United States Mary Ann Liebert, Inc 01.06.2015
• Subjects: Animals; CD8-Positive T-Lymphocytes - immunology; Cyclophosphamide; Cytomegalovirus; Female; Herpesviridae Infections - immunology; Herpesviridae Infections - virology; Immediate-Early Proteins - immunology; Immunocompromised Host - immunology; Interferon-gamma - immunology; Lung - immunology; Lung - pathology; Lymphocyte Count; Lymphopenia - immunology; Lymphopenia - virology; Mice; Mice, Inbred BALB C; Murine cytomegalovirus; Muromegalovirus - immunology; Original Research Articles; Original s; Pneumonia - immunology; Pneumonia - virology; T-Lymphocyte Subsets - immunology
• ISSN: 0882-8245; 1557-8976
• DOI: 10.1089/vim.2015.0005

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.