Quantitative and functional diversity of cross-reactive EBV-specific CD8+ T cells in a longitudinal study cohort of lung transplant recipients.
BACKGROUND
Cross-reactive antiviral memory T cells constitute a significant proportion of the alloresponse, potentially playing a pivotal role in adverse posttransplant outcomes in human leukocyte antigen (HLA)-mismatched allografts. We explored the longitudinal dynamics of cross-reactive HLA-B8-restricted Epstein-Barr virus-specific CD8+ T cells directed toward the EBNA3A epitope FLRGRAYGL (FLR) in lung transplant recipients (LTRs) to determine whether their corecognition of HLA-B*4402 expressed on the allograft contributed to poorer posttransplant outcomes.


METHODS
Cross-reactive FLR-specific CD8+ T cells were measured in the peripheral blood mononuclear cells and bronchoalveolar lavage fluid in 11 HLA-B8+ LTR, who had received HLA-B44+ lung allograft, after in vitro autologous (FLR pulsed) or allogeneic stimulation by multiparameter flow cytometry.


RESULTS
FLR-specific CD8+ T cells were detectable ex vivo and after 13 days following in vitro peptide stimulation of peripheral blood mononuclear cells. Individual LTR and demonstrated diverse functional profiles of either cytokine production and/or cytotoxic potential (interferon-g+, interferon-g+CD107a+ and CD107a+ subsets). However, cells isolated from bronchoalveolar lavage exhibited a skewed functional phenotype toward CD107a expression alone, indicating cytotoxic-producing but not cytokine-producing capabilities. In addition, our findings suggested that the presence of cross-reactive FLR-specific CD8+ T cells may influence the alloreactive hierarchy directed against the allograft, although they were not associated with poorer short- or long-term clinical outcomes in the absence of Epstein-Barr virus reactivation and in the setting of current immunosuppression and antiviral prophylaxis protocols.


CONCLUSIONS
We report, for the first time, the longitudinal measurement of cross-reactive FLR-specific CD8 T cells within a clinical transplantation framework.
Department of Medicine, Monash University, Central Clinical School, The Alfred Hospital, Melbourne, Victoria, Australia. nicole.mifsud@monash.edu
Nicole A
NA
Mifsud
Thi Hoang Oanh
TH
Nguyen
Brian D
BD
Tait
Tom C
TC
Kotsimbos
D001402:B-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D015331:Cohort Studies; D003429:Cross Reactions; D004279:DNA, Viral / Q000097:blood; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D014644:Genetic Variation; D015235:HLA-B Antigens / Q000276:immunology; D059948:HLA-B44 Antigen; D015795:HLA-B8 Antigen / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007519:Isoantigens / Q000276:immunology; D016040:Lung Transplantation / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
D004279:DNA, Viral; D015235:HLA-B Antigens; D059948:HLA-B44 Antigen; D015795:HLA-B8 Antigen; D007519:Isoantigens; D011948:Receptors, Antigen, T-Cell