Title: γδ T Cells and Resolution of Cytomegalovirus Infection in an HIV/HCV Coinfected Patient after Liver Transplantation
Abstract: Cytomegalovirus (CMV) infection is a frequent transplant complication. Anti-CMV responses in allograft recipients have been extensively studied, only few reports addressing γδ T lymphocytes role (1, 2). γδ T cells may play a natural antiviral role (3), and kidney allograft recipients during CMV infection undergo a massive expansion of circulating γδ T cells (4). The occurrence of a primary CMV infection in a highly immunosuppressed patient may represent a model about the role of innate immunity in this setting. We analyzed a 41-year-old human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patient undergoing primary CMV infection after orthotopic liver transplantation (OLT). The donor was negative for antibodies to HIV-1/2 or HCV, but positive for CMV IgG. At day 42 after OLT, the patient suffered from fever (>38°C for more than 2 days), leukopenia (<4×109 leukocytes/L in >2 consecutive samples) and malaise. CMV infection resolved within day 60. No CMV prophylaxis or treatment were performed and CMV infection was retrospectively diagnosed. Thus, resolution was only dependent on the host-response. At day 45, CMV-DNA was transiently positive; anti-CMV IgM and IgG were observed at days 99 and 112, respectively. As Vδ1 T lymphocytes are specifically expanded by both chronic HIV (5, 6) or acute CMV infections (1, 2), the distribution of this γδ T cell subset was compared to the kinetics of CMV- and HIV-specific CD8 T cell responses (Fig. 1). Lymphocytes showed a transient decrease at CMV viremia and disease onset (day 45, Fig. 1A). Vδ1 T cells increased at day 2, decreased at the time of clinical disease at day 45 and dropped at day 72, suggesting a γδ-specific T cell exhaustion and/or tissue migration. A subsequent increase of Vδ1 T cells was observed at day 112. As shown in Figure 1B, during the preOLT period Vδ1 T cells were composed mostly of terminally differentiated effector memory Temra (CD27-CD45RA+) cells (7); 2 days after OLT, both Vδ1 naïve (CD27+CD45RA+) and Temra cells increased. Differently, the peak of naïve Vδ1 T cells that follows the resolution of CMV infection (at day 112) may represent a homeostatic response.FIGURE 1.: Vδ1 T lymphocytes and CMV- and HIV-specific CD8 responses in an HIV/HCV coinfected patient undergoing acute CMV infection after OLT. (A) Circulating total lymphocyte number and Vδ1 T cells number are shown. (B) Vδ1 differentiation subsets are shown as determined by flow cytometry. In particular, Vδ1 Naïve CD27+CD45RA+ and terminally differentiated effector memory CD27-CD45RA+ cells (Temra) numbers are shown. (C) CMV-specific CD8 response to CMV antigens, measured as IFN-γ production, is shown. (D) HIV-specific CD8 response to Nef, Gag, and Tat HIV-1 proteins, measured as IFN-γ production by flow cytometry, are shown. In both panels C and D, IFN-γ producing cell numbers among 105 CD8 T cells are shown.Before OLT, no CD8 response to CMV was found (Fig. 1C). CMV-specific CD8 T cells appeared at day 2, were stable up to day 72, with a peak at day 112 (Fig. 1C). When HIV Gag-, Nef- and Tat-specific CD8 responses were monitored (Fig. 1D), a slight increase of responding cells was found at day 2 after OLT, but dropped at day 72. γδ T cells are more resistant to immunosuppressive drugs than αβ T cells (8), and they are numerous in the mucosal epithelium, which is a preferred site of CMV replication (9). Moreover, Vδ2-negative T cell clones from kidney transplant recipients display strong reactivity against CMV-infected cells, being able to kill CMV-infected targets (10). Accordingly, this study shows for the first time that Vδ1 Temra effector cells increased before the onset of CMV acute symptoms, indicating that gamma/delta T cells may play a relevant antiviral role also in transplanted HIV/HCV immunocompromised host; their monitoring may be indicative of subclinical infections and ability to control CMV infection. Gianpiero D'Offizi Cristiana Gioia Federico Martini Ilaria Volpi Mariacarmela Solmone Fabrizio Poccia Pasquale Narciso National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS Rome, Italy Giovanni Vennarecci Giuseppe Maria Ettore Mario Antonini Eugenio Santoro Department of Surgical Oncology Division of Digestive Surgery and Liver Transplantation Regina Elena Cancer Institute Rome, Italy Giampiero Carosi Department of Infectious and Tropical Diseases University of Brescia Brescia, Italy