Cytomegalovirus-Induced γδ T Cells During Rejection: An Ambivalent T Cell

Abstract

To the Editor: From a large cohort, Shi et al recently observed that cytomegalovirus (CMV) D+R- serostatus was associated with protection against late acute rejection of liver allografts (1.Shi XL de Mare-Bredemeijer EL Tapirdamaz O CMV primary infection is associated with donor-specific T cell hyporesponsiveness and fewer late acute rejections after liver transplantation.Am J Transplant. 2015; 15 (et al): 2431-2442Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). Although this finding appears very interesting, some immunological hypotheses proposed in this article deserve several comments. First, the conclusion that CD8+ T cells from CMV-infected patients displayed a donor-specific hyporesponsiveness may be challenged because (1.Shi XL de Mare-Bredemeijer EL Tapirdamaz O CMV primary infection is associated with donor-specific T cell hyporesponsiveness and fewer late acute rejections after liver transplantation.Am J Transplant. 2015; 15 (et al): 2431-2442Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar) there is no difference in the level of donor-specific alloresponse at 6 months posttransplantation between D+R-, R+, and D-R- patients; (2.Couzi L Pitard V Moreau JF Merville P Dechanet-Merville J. Direct and indirect effects of cytomegalovirus-induced gammadelta T cells after kidney transplantation.Front Immunol. 2015; 6: 3Crossref PubMed Scopus (50) Google Scholar) no change in the level of donor-specific alloresponse was evaluated between pretransplantation and 6 months; and (3.Puig-Pey I Bohne F Benitez C Characterization of gammadelta T cell subsets in organ transplantation.Transplant Int. 2010; 23 (et al): 1045-1055Crossref PubMed Scopus (55) Google Scholar) the assessment of the response to third party as a control representative of a normal immune response is questionable. These data could also be interpreted as an increase of the third-party alloresponse observed at 6 months posttransplantation in D+R- patients, which could reflect the emergence of CMV-specific CD8+ T cells. Second, Kwekkeboom’s group reported that CMV primary infection patients had high levels of Vδ1 γδ T cells, which have been associated with operational tolerance after liver transplantation by Sanchez-Fueyo’s team a few years ago. However, before that, we and others had demonstrated that Vδ1, Vδ3, and Vδ5 γδ T cells (also designated as Vδ2neg γδ T cells) underwent a dramatic and stable expansion after CMV infection, in all solid organ transplant recipients, immunodeficient children, neonates, pregnant women, and healthy individuals. Similarly to CMV-specific CD8+ T cells, they exhibit an effector/memory TEMRA phenotype. In vitro, Vδ2neg γδ T cell lines exhibit a robust cytotoxic effector function against CMV-infected cells. In vivo, γδ T cells confer protection against murine CMV (2.Couzi L Pitard V Moreau JF Merville P Dechanet-Merville J. Direct and indirect effects of cytomegalovirus-induced gammadelta T cells after kidney transplantation.Front Immunol. 2015; 6: 3Crossref PubMed Scopus (50) Google Scholar). Therefore, Shi et al confirm this association since they demonstrated that CMV primary infection patients showed the highest Vδ1/Vδ2 γδ T cell ratio. In 2010, Sanchez-Fueyo’s team revised their seminal interpretation and showed that the overlap in the distribution of markers based on γδ T cells prevented their use as potentially diagnostic biomarkers of tolerance (3.Puig-Pey I Bohne F Benitez C Characterization of gammadelta T cell subsets in organ transplantation.Transplant Int. 2010; 23 (et al): 1045-1055Crossref PubMed Scopus (55) Google Scholar). According to them, the Vδ1/Vδ2 γδ T cell ratio was thus related to CMV infection and not restricted to tolerant liver recipients, consistent with our previous observations. In an opposite view to this association of Vδ1/Vδ2 γδ T cell ratio with operational tolerance, we even recently involved Vδ2neg γδ T cells as a new effector in rejection. γδ T cells express a broad range of activatory molecules and among them the CD16 molecule (FcγRIIIA), which is required for antibody-dependent cell cytotoxicity (ADCC). We showed that CMV infection deeply reshapes the CD16+ lymphocyte compartment composition in CMV+ recipients who exhibit an equal amount of CD16+ natural killer (NK) cells and CD16+ Vδ2neg γδ T cells (4.Couzi L Pitard V Sicard X Antibody-dependent anti-cytomegalovirus activity of human gammadelta T cells expressing CD16 (FcgammaRIIIa).Blood. 2012; 119 (et al): 1418-1427Crossref PubMed Scopus (93) Google Scholar). We also demonstrated that CMV-induced CD16+ Vδ2neg γδ T cells could perform ADCC as well as NK cells by interacting with donor-specific antibodies and contribute to antibody-mediated microcirculation injuries during rejection (5.Bachelet T Couzi L Pitard V Cytomegalovirus-responsive gammadelta T cells: Novel effector cells in antibody-mediated kidney allograft microcirculation lesions.J Am Soc Nephrol. 2014; 25 (et al): 2471-2482Crossref PubMed Scopus (32) Google Scholar). This implication of CMV-induced Vδ2neg γδ T cells in antibody-mediated rejection seemingly contrasts with the regulatory function attributed to Vδ1 γδ T cells in this article (Figure 1). The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.