Localization of Viral Epitope-Specific CD8 T Cells during Cytomegalovirus Latency in the Lungs and Recruitment to Lung Parenchyma by Airway Challenge Infection.

Franziska Blaum,Matthias J Reddehase,Niels A W Lemmermann,Dominika Lukas

doi:10.3390/life11090918

Abstract

Interstitial pneumonia is a life-threatening clinical manifestation of cytomegalovirus infection in recipients of hematopoietic cell transplantation (HCT). The mouse model of experimental HCT and infection with murine cytomegalovirus revealed that reconstitution of virus-specific CD8+ T cells is critical for resolving productive lung infection. CD8+ T-cell infiltrates persisted in the lungs after the establishment of latent infection. A subset defined by the phenotype KLRG1+CD62L− expanded over time, a phenomenon known as memory inflation (MI). Here we studied the localization of these inflationary T effector-memory cells (iTEM) by comparing their frequencies in the intravascular and transmigration compartments, the IVC and TMC, respectively, with their frequency in the extravascular compartment (EVC), the alveolar epithelium. Frequencies of viral epitope-specific iTEM were comparable in the IVC and TMC but were reduced in the EVC, corresponding to an increase in KLRG1−CD62L− conventional T effector-memory cells (cTEM) and a decrease in functional IFNγ+CD8+ T cells. As maintained expression of KLRG1 requires stimulation by antigen, we conclude that iTEM lose KLRG1 and convert to cTEM after transmigration into the EVC because pneumocytes are not latently infected and, therefore, do not express antigens. Accordingly, antigen re-expression upon airway challenge infection recruited virus-specific CD8+ T cells to TMC and EVC.

Highlights

The expanding cells represent a subset of CD8+ T cells that is characterized by the cell surface marker phenotype KLRG1+ CD62L− [49], for which we have proposed the acronym iTEM for “inflationary T effector-memory cells” to distinguish them from the conventional
To isolate leucocytes, including CD8+ T cells, from the compartments of latently infected lungs, a gentle bronchoalveolar lavage was performed as a first step to retrieve cells that are only loosely attached to parenchymal epithelial cells of the alveoli, defining the extravascular compartment (EVC)
This yields intravascular leucocytes that are more firmly attached to Endothelial cells (EC) lining the lung capillaries, cells in the process of transmigration, and extravascular cells localizing to the connective tissue of the interstitium

Summary

Introduction

Human cytomegalovirus (hCMV) is a prototype member of the β-subfamily of the herpes virus family [1]. Whereas primary infection passes mostly undiagnosed without overt clinical symptoms or organ disease when held in check by an intact innate and adaptive immune system in the otherwise healthy, immunocompetent host, unrestricted cytopathogenic tissue infection can lead to multiple-organ failure with often lethal outcome in an immunocompromised host [2,3,4]. A significant public health and economic impact [5,6], and the main argument for the development of a CMV vaccine [7,8,9,10], results from birth defects caused by hCMV in an immunologically immature embryo/fetus after congenital infection following diaplacental transmission of the virus [11,12] after primary or recurrent infection during pregnancy [13]

Methods

Results

Conclusion