High levels of CMV-IE-1-specific memory T cells are associated with less alloimmunity and improved renal allograft function

Transpl Immunol. 2009 Mar;20(4):238-42. doi: 10.1016/j.trim.2008.11.002. Epub 2008 Nov 24.

Abstract

Background: Cytomegalovirus (CMV) infection has been associated with allograft rejection in solid organ transplantation. However, the immunologic mechanisms behind this observation have not been elucidated. One proposed mechanism is direct cross-reactivity of antiviral T-cells with allogeneic MHC/peptide complexes, a process termed heterologous immunity. Another model favours indirect stimulation of alloimmunity by CMV-induced proinflammatory cytokines and upregulation of MHC class II and adhesion molecules. Recently, we found that protection from CMV disease was correlated with high levels of CMV-immediate early-1 (IE-1) specific IFN-gamma-producing T-cell responses in heart and lung transplant recipients. The aim of this study was to define the relation of CMV-specific T-cell responses to acute rejection, donor-reactive memory T cells, and allograft function after kidney transplantation.

Methods: To address this issue, IFN-gamma-producing T-cell responses following ex-vivo stimulation with pools of overlapping peptides representing the CMV pp65 and IE-1 proteins, as well as donor-reactive IFN-gamma-producing T-cells were determined at multiple time points before (pre-Tx) and during the first 6 months posttransplant (post-Tx) in 36 kidney transplant recipients using an enzyme linked immunoabsorbent spot assay (ELISPOT).

Results: CMV-specific T cells were not exclusively detectable in CMV seropositive patients, as 3/12 seronegative patients had significant pre- and post-Tx pp65/IE-1-specific T-cell responses. In patients with detectable anti-CMV antibody or T-cell responses, no difference in CMV-specific T-cell frequencies was found between patients with versus without acute rejection. However, early (week 1, r=0.457, p=0.037) and average IE-1-specific T-cell responses (r=-0.415, p=0.032) during 6 months post-Tx showed a significant inverse correlation with average post-Tx donor-reactive T-cell responses. Furthermore, average post-Tx IE-1-specific T-cell responses correlated significantly with 6 and 12 months glomerular filtration rate (GFR). In contrast, pp65-specific T-cell responses did not correlate with donor-reactive T cells or graft function. Only 2/36 patients developed CMV disease, both showing very weak IE-1-specific T-cell responses during the whole monitoring period.

Conclusion: No evidence for heterologous immunity could be found in patients with high levels of CMV-specific T cells. On the contrary, less alloreactivity and improved graft function were found in patients with strong IE-1-specific T-cell responses. These results emphasize the importance of immediate early antigens (IE) as targets for T-cell immunity to CMV. We hypothesize that IE-1-specific T cells might effectively suppress IE-1-induced indirect effects such as inflammation and upregulation of MHC class II and adhesion molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cytomegalovirus / immunology*
  • Cytomegalovirus Infections / blood
  • Cytomegalovirus Infections / immunology*
  • Female
  • Glomerular Filtration Rate / immunology
  • Graft Survival / immunology*
  • Humans
  • Immediate-Early Proteins / chemistry
  • Immediate-Early Proteins / immunology*
  • Immediate-Early Proteins / metabolism
  • Immunologic Memory
  • Interferon-gamma / metabolism
  • Isoantibodies / immunology
  • Kidney Transplantation / immunology*
  • Lymphocyte Activation
  • Male
  • Middle Aged
  • Peptides / chemical synthesis
  • Peptides / immunology
  • Peptides / metabolism*
  • Phosphoproteins / chemistry
  • Phosphoproteins / immunology
  • Phosphoproteins / metabolism
  • T-Cell Antigen Receptor Specificity
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / pathology
  • Transplantation, Homologous
  • Viral Matrix Proteins / chemistry
  • Viral Matrix Proteins / immunology
  • Viral Matrix Proteins / metabolism

Substances

  • IE1 protein, cytomegalovirus
  • Immediate-Early Proteins
  • Isoantibodies
  • Peptides
  • Phosphoproteins
  • Viral Matrix Proteins
  • cytomegalovirus matrix protein 65kDa
  • Interferon-gamma