Recognition of distinct cross-reactive virus-specific CD8+ T cells reveals a unique TCR signature in a clinical setting.
Human CMV still remains problematic in immunocompromised patients, particularly after solid organ transplantation. CMV primary disease and reactivation greatly increase the risks associated with incidences of chronic allograft rejection and decreased survival in transplant recipients. But whether this is due to direct viral effects, indirect viral effects including cross-reactive antiviral T cell immunopathology, or a combination of both remains undetermined. In this article, we report the novel TCR signature of cross-reactive HLA-A*02:01 (A2) CMV (NLVPMVATV [NLV])-specific CD8(+) T cells recognizing a specific array of HLA-B27 alleles using technical advancements that combine both IFN-γ secretion and multiplex nested RT-PCR for determining paired CDR3α/β sequences from a single cell. This study represents the first evidence, to our knowledge, of the same A2-restricted cross-reactive NLV-specific TCR-α/β signature (TRAV3TRAJ31_TRBV12-4TRBJ1-1) in two genetically distinct individuals. Longitudinal posttransplant monitoring of a lung transplant recipient (A2, CMV seropositive) who received a HLA-B27 bilateral lung allograft showed a dynamic expansion of the cross-reactive NLV-specific TCR repertoire before CMV reactivation. After resolution of the active viral infection, the frequency of cross-reactive NLV-specific CD8(+) T cells reduced to previremia levels, thereby demonstrating immune modulation of the T cell repertoire due to antigenic pressure. The dynamic changes in TCR repertoire, at a time when CMV reactivation was subclinical, illustrates that prospective monitoring in susceptible patients can reveal nuances in immune profiles that may be clinically relevant.
Department of Medicine, Monash University, Central Clinical School, The Alfred Centre, Melbourne, Victoria 3004, Australia; Department of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Melbourne, Victoria 3004, Australia;
Thi H O
TH
Nguyen
Department of Medicine, Monash University, Central Clinical School, The Alfred Centre, Melbourne, Victoria 3004, Australia; Department of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Melbourne, Victoria 3004, Australia;
Louise C
LC
Rowntree
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia; and.
Daniel G
DG
Pellicci
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia; and.
Nicola L
NL
Bird
Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens, GA 30602.
Andreas
A
Handel
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia; and.
Lars
L
Kjer-Nielsen
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia; and.
Katherine
K
Kedzierska
Department of Medicine, Monash University, Central Clinical School, The Alfred Centre, Melbourne, Victoria 3004, Australia; Department of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Melbourne, Victoria 3004, Australia;
Tom C
TC
Kotsimbos
Department of Medicine, Monash University, Central Clinical School, The Alfred Centre, Melbourne, Victoria 3004, Australia; Department of Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Melbourne, Victoria 3004, Australia; nicole.mifsud@monash.edu.
Nicole A
NA
Mifsud
D064591:Allografts; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000276:immunology*; D005260:Female; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016040:Lung Transplantation; D008297:Male; D008991:Monitoring, Physiologic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*
C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C573415:IFNG protein, human; D016693:Receptors, Antigen, T-Cell, alpha-beta; D007371:Interferon-gamma