title: Cytomegalovirus reactivation following allogeneic stem cell transplantation is associated with the presence of dysfunctional antigen-specific CD8+ T cells.
abstract: Cytomegalovirus (CMV) infection causes significant morbidity and mortality in the setting of immunodeficiency, including the immune reconstitution phase following allogeneic stem cell transplantation (SCT). We assessed CMV-specific CD4(+) and CD8(+) T-cell responses in 87 HLA-A*0201-positive (A2+) and/or B*0702-positive (B7+) allogeneic stem cell transplant recipients using HLA-peptide tetramer staining and cytokine flow cytometry (CFC) to examine the association of CMV-specific immune reconstitution and CMV antigenemia following SCT. Strong CMV-specific T-cell responses recovered in most subjects (77 of 87, 88%) after SCT. Frequencies of CMV-specific CD8(+) T cells were significantly higher in those subjects who experienced early antigenemia relative to those who did not (2.2% vs 0.33%, P =.0002), as were frequencies of CMV-specific CD4(+) T cells (1.71% vs 0.75%, P =.002). Frequencies of CMV-specific CD8(+) T cells were also higher in subjects experiencing late antigenemia (2.4% vs 0.57%). When we combined tetramer staining and an assessment of cytokine production in a single assay, we found that individuals who experienced CMV antigenemia had lower tumor necrosis factor-alpha (TNF-alpha)-producing fractions of tetramer-staining CMV-specific CD8(+) T cells than subjects who did not (25% vs 65%, P =.015). Furthermore, individuals at high risk for CMV reactivation, including patients with acute graft-versus-host disease and those receiving steroids, had low fractions of cytokine-producing CMV-specific CD8(+) T cells (25% and 27%, respectively). These data suggest that the inability to control CMV reactivation following allogeneic SCT is due to the impaired function of antigen-specific CD8(+) T cells rather than an inability to recover sufficient numbers of CMV-specific T cells.
authors.affiliation: Transplant Immunology Section, Department of Blood and Marrow Transplantation, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Evren
authors.initials: E
authors.lastname: Ozdemir
authors.forename: Lisa S
authors.initials: LS
authors.lastname: St  John
authors.forename: Geraldine
authors.initials: G
authors.lastname: Gillespie
authors.forename: Sarah
authors.initials: S
authors.lastname: Rowland-Jones
authors.forename: Richard E
authors.initials: RE
authors.lastname: Champlin
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Molldrem
authors.forename: Krishna V
authors.initials: KV
authors.lastname: Komanduri
mesh_terms: D000328:Adult; D000368:Aged; D000956:Antigens, Viral / Q000097:blood / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D003430:Cross-Sectional Studies; D003587:Cytomegalovirus / Q000254:growth & development / Q000276:immunology* / Q000502:physiology; D005260:Female; D019337:Hematologic Neoplasms / Q000276:immunology / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D014184:Transplantation, Homologous / Q000009:adverse effects; D014775:Virus Activation / Q000276:immunology*
chemical_list: D000956:Antigens, Viral