The Presence of HLA-E-Restricted, CMV-Specific CD8+ T Cells in the Blood of Lung Transplant Recipients Correlates with Chronic Allograft Rejection

Abstract

The human cytomegalovirus (CMV) immune evasion protein, UL40, shares an identical peptide sequence with that found in the leader sequence of many human leukocyte antigen (HLA)-C alleles and when complexed with HLA-E, can modulate NK cell functions via interactions with the CD94-NKG2 receptors. However the UL40-derived sequence can also be immunogenic, eliciting robust CD8+ T cell responses. In the setting of solid organ transplantation these T cells may not only be involved in antiviral immunity but also can potentially contribute to allograft rejection when the UL40 epitope is also present in allograft-encoded HLA. Here we assessed 15 bilateral lung transplant recipients for the presence of HLA-E-restricted UL40 specific T cells by tetramer staining of peripheral blood mononuclear cells (PBMC). UL40-specific T cells were observed in 7 patients post-transplant however the magnitude of the response varied significantly between patients. Moreover, unlike healthy CMV seropositive individuals, longitudinal analyses revealed that proportions of such T cells fluctuated markedly. Nine patients experienced low-grade acute cellular rejection, of which 6 also demonstrated UL40-specific T cells. Furthermore, the presence of UL40-specific CD8+ T cells in the blood was significantly associated with allograft dysfunction, which manifested as Bronchiolitis Obliterans Syndrome (BOS). Therefore, this study suggests that minor histocompatibility antigens presented by HLA-E can represent an additional risk factor following lung transplantation.

HCMV triggers frequent and persistent UL40-specific unconventional HLA-E-restricted CD8 T-cell responses with potential autologous and allogeneic peptide recognition

“…These values are the highest reported for this unconventional subset ex vivo . Previous studies established ex vivo percentages of HLA-E-restricted anti-UL40 CD8 T cells from 0.05% [ 31 ] to 14% [ 30 , 32 ]. Thus, HLA-E-restricted responses mirror HLA-Ia-restricted responses in both frequency and magnitude.…”

“…HLA-E/UL40 (HLA-E UL40 ) complexes also trigger TCR-dependent activation of a subset of CD8 αβ T cells [ 28 – 30 ]. UL40-specific/anti-HCMV HLA-E–restricted CD8 cytotoxic T-cell responses have been reported in healthy donors and in kidney and lung transplant recipients and associated with a possible harmful impact on graft endothelial cells [ 30 ] and allograft survival [ 31 ]. Characterization of these CD8 T-cell subsets in healthy and transplanted population remains sparse and no longitudinal study is available.…”

The Microtubule Inhibitor Podofilox Inhibits an Early Entry Step of Human Cytomegalovirus

“…In the immunocompromised and neonatal populations, CMV is a major source of morbidity and mortality [2]. CMV is the leading cause of permanent congenital disability in the United States [3] and also a source of organ transplant failure [4,5,6]. …”

Preliminary Study of Fourteen AIDS-Associated Lung Complications from Imaging,Pathology and Microbiology

“…Cytomegalovirus can spread into every tissues of body that can cause an injury on host cell. In addition, its infection can also produce side impact on immunity [28]. Scenario of ground glass, consolidation of lung, grid-like formation, thickened bronchial wall is fund by CT.…”