Differential CMV-specific CD8+ effector T cell responses in the lung allograft predominate over the blood during human primary infection.
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.
Pipeling
Matthew R
MR
Division of Pulmonary and Critical Care Medicine, Department of Pathology and Medical Microbiology, Johns Hopkins University, School of Medicine, Baltimore, MD 21224, USA.
West
Erin E
EE
Osborne
Christine M
CM
Whitlock
Amanda B
AB
Dropulic
Lesia K
LK
Willett
Matthew H
MH
Forman
Michael
M
Valsamakis
Alexandra
A
Orens
Jonathan B
JB
Moller
David R
DR
Lechtzin
Noah
N
Migueles
Stephen A
SA
Connors
Mark
M
McDyer
John F
JF
D000208:Acute Disease; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000097:blood* / Q000175:diagnosis / Q000276:immunology* / Q000821:virology; D005260:Female; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D016040:Lung Transplantation / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000276:immunology; D011014:Pneumonia / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology; D014763:Viral Matrix Proteins / Q000276:immunology; D014766:Viremia / Q000276:immunology
D016207:Cytokines; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D017493:Leukocyte Common Antigens