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Differential CMV-Specific CD8⁺ Effector T Cell Responses in the Lung Allograft Predominate over the Blood during Human Primary Infection¹

Matthew R. Pipeling^*, Erin E. West^*, Christine M. Osborne, Amanda B. Whitlock^*, Lesia K. Dropulic, Matthew H. Willett^*, Michael Forman, Alexandra Valsamakis, Jonathan B. Orens^*, David R. Moller^*, Noah Lechtzin^*, Stephen A. Migueles, Mark Connors and John F. McDyer^2,*

^* Division of Pulmonary and Critical Care Medicine, Division of Infectious Diseases, and Department of Pathology and Medical Microbiology, Johns Hopkins University, School of Medicine, Baltimore, MD 21224; and Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

Acquisition of T cell responses during primary CMV infection in lung transplant recipients (LTRs) appear critical for host defense and allograft durability, with increased mortality in donor⁺/recipient^– (D⁺R^–) individuals. In 15 D⁺R^– LTRs studied, acute primary CMV infection was characterized by viremia in the presence or absence of pneumonitis, with viral loads higher in the lung airways/allograft compared with the blood. A striking influx of CD8⁺ T cells into the lung airways/allograft was observed, with inversion of the CD4⁺:CD8⁺ T cell ratio. De novo CMV-specific CD8⁺ effector frequencies in response to pooled peptides of pp65 were strikingly higher in lung mononuclear cells compared with the PBMC and predominated over IE1-specific responses and CD4⁺ effector responses in both compartments. The frequencies of pp65-specific cytokine responses were significantly higher in lung mononuclear cells compared with PBMC and demonstrated marked contraction with long-term persistence of effector memory CD8⁺ T cells in the lung airways following primary infection. CMV-tetramer⁺CD8⁺ T cells from PBMC were CD45RA^– during viremia and transitioned to CD45RA⁺ following resolution. In contrast, CMV-specific CD8⁺ effectors in the lung airways/allograft maintained a CD45RA^– phenotype during transition from acute into chronic infection. Together, these data reveal differential CMV-specific CD8⁺ effector frequencies, immunodominance, and polyfunctional cytokine responses predominating in the lung airways/allograft compared with the blood during acute primary infection. Moreover, we show intercompartmental phenotypic differences in CMV-specific memory responses during the transition to chronic infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by U.S. Public Health Service Grants HL-068682 and AI-072537 (to J.F.M.).

² Address correspondence and reprint requests to Dr. John F. McDyer, Johns Hopkins University, Department of Medicine, 5501 Bayview Circle, Room 4B51, Baltimore, MD 21224. E-mail address: jmcdyer{at}jhmi.edu

³ Abbreviations used in this paper: SOT, solid organ transplant; BAL, bronchoalveolar lavage; D⁺R^–, donor⁺/recipient^–; ICS, intracellular cytokine staining; LMNC, lung mononuclear cell; LTR, lung transplant recipient.