Recovery of CMV-Specific CD8+ T Cells and Tregs after Allogeneic Peripheral Blood Stem Cell Transplantation

Abstract

Recovery of cytomegalovirus (CMV)-specific CD8+ T cells after allogeneic stem cell transplantation (SCT) is critical for protection against CMV infection and disease. Moreover, Foxp3+CD4+CD25(high) regulatory T cells (Tregs) are a major regulator of adaptive immunity, preventing graft-versus-host disease (GVHD) and so promoting timely and complete immune recovery. The aim of our study was to evaluate the recovery of circulating tetramer-based CMV-specific CD8+ T cells and T regs in 46 patients after allogeneic peripheral blood SCT (PBSCT). CMV infection and/or disease was observed in 7% and 94% of patients with or without CMV-specific CD8+ T cells recovery (P < .001), and in 77% and 4% of patients with or without acute GVHD (aGVHD) (P < .001), respectively. T regs values were higher in patients without than with CMV infection and/or disease at 2 (P < .001) and 3 months (P < .001) after allogeneic PBSCT, respectively. Moreover, we observed a positive correlation between T regs and the recovery of CMV-specific CD8+ T cells at 2 (r = .61, P < .0001) and 3 (r = .72, P < .00001) months, respectively. Tregs were higher in patients without than with aGVHD at 1, 2 (P < .001) and 3 months (P < .0001), respectively. At multivariate logistic regression, aGVHD (odds ratio [OR]: 2.60, 95% confidence interval [CI] [1.3-5.0], P = .0006) and CMV-specific CD8+ T cells recovery (OR:2.25, 95% CI [1.2-4.8], P = .05) were correlated with CMV infection and/or disease, whereas no correlation was found for Tregs, absolute neutrophil count, patients' and donors' age, disease status pretransplantation, type of disease, and CMV serology. Taken together, our data may suggest the existence of a correlation between Tregs and the recovery of CMV-specific CD8+ T cells; Tregs may preserve an optimal microenvironment for the reconstitution of functional immunity and mediate protective effects against aGVHD.

Reconstitution of CMV pp65 and IE-1-specific IFN-γ CD8+ and CD4+ T-cell responses affording protection from CMV DNAemia following allogeneic hematopoietic SCT

“…6 Moreover, threshold levels of certain CMV-specific T-cell populations presumably affording protection from active CMV infection and disease have been temptatively established, though their clinical utility awaits further validation. [9][10][11][12][13][14][15][16] In a pilot study, we showed that quantification of CD8 þ and CD4 þ T cells producing IFN-g on stimulation with two peptide libraries encompassing the entire sequence of pp65, and IE-1 allowed the identification of patients presumably protected from CMV DNAemia early after transplantation.…”

Early detection of cytomegalovirus-specific cytotoxic T lymphocytes against cytomegalovirus antigenemia in human leukocyte antigen haploidentical hematopoietic stem cell transplantation

“…As an alternative donor source for SCT, the success of haplo-SCT requires T cell depletion and/or posttransplantation augmented immunosuppression to prevent lethal graft-versushost disease (GVHD). These levels of immunosuppression may lead to the delayed reconstitution of CMV-specific T lymphocyte immunity and to a higher incidence of CMV infection following SCT [8,10]. In our protocol of unmanipulated haplo-SCT with methylprednisolone as a GVHD prophylaxis, the incidence of CMV antigenemia increased to approximately 80 % [11,12].…”

“…To identify and quantify CMV-CTLs, major histocompatibility complex (MHC) multimer-based technology, such as using tetramers, has been recently established as a convenient tool by flow cytometry [4]. Using this method, CMV-CTL reconstitution of more than a certain level has been reported to be protective against CMV-associated complications in SCT patients [5][6][7][8]. On the other hand, it has been shown that the presence of CMV antigenemia results in more rapidly induced CMV-CTL development [7,9].…”

Reconstitution of Protective Immune Responses against Cytomegalovirus and Varicella Zoster Virus Does Not Require Disease Development in Pediatric Recipients of Umbilical Cord Blood Transplantation

“…Although CD4 + T cell counts doubled between 2 and 3 mo (median, 25 + and CD8 + T cell counts remained below normal at 6 mo posttransplantation, although some subjects had already attained normal T lymphocyte counts (Fig. 1A) (51,52).…”

“…Moreover, the high sensitivity of PCR detection may lead to overtreatment of patients who would not have otherwise progressed to overt CMV disease (23). Recent tetramer-based studies showed that rapid recovery of CMV-specific CD8 + T lymphocytes was associated with a reduced incidence of CMV-related complications in allogeneic hematopoietic stem cell transplantation (HSCT) recipients (24,25). Production of IFN-g by CMV-specific CD4 + and CD8 + T cells was closely associated with control of CMV antigenemia and circulating levels of CMV DNA (DNAemia) following allogeneic HSCT in some studies (26,27) but not in others (28,29), all of which were studies in which only a few pediatric UCBT recipients were enrolled.…”