Rapid T cell repopulation after rabbit anti-thymocyte globulin (rATG) treatment is driven mainly by cytomegalovirus

Abstract

Summary Rabbit anti-thymocyte globulin (rATG) induces a long-lasting lymphocytopenia. CD4+ T cells remain depleted for up to 2 years, whereas the CD8+ T cell compartment is refilled rapidly by highly differentiated CD27–CD45RA+CD57+effector-type cells. Because the presence of these highly differentiated CD8+ T cells has been associated with cytomegalovirus (CMV) infection, we questioned to what extent restoration of CMV T cell immunity contributes to the re-emergence of T cells following rATG treatment. We compared T cell repopulation in six CMV-seropositive patients with CMV reactivation (reactivating CMV+) to that in three CMV+ patients without reactivation (non-reactivating CMV+), and to that in three CMV-seronegative recipients receiving a kidney from a CMV-seronegative donor (CMV−/−). All patients received rATG because of acute allograft rejection. Total CD4 and CD8 counts, frequency and phenotype of virus-specific CD8+ T cells were determined. In reactivating CMV+ patients, total CD8+ T cells reappeared rapidly, whereas in non-reactivating CMV+ patients they lagged behind. In CMV−/− patients, CD8+ T cell counts had not yet reached pretransplant levels after 2 years. CMV reactivation was indeed followed by a progressive accumulation of CMV-specific CD8+ T cells. During lymphocytopenia following rATG treatment, serum interleukin (IL)-7 levels were elevated. Although this was most prominent in the CMV-seronegative patients, it did not result in an advantage in T cell repopulation in these patients. Repopulated CD8+ T cells showed increased skewing in their Vβ repertoire in both CMV−/− and reactivating CMV-seropositive patients. We conclude that rapid T cell repopulation following rATG treatment is driven mainly by CMV.