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


CONCLUSIONS
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.
Nickel
Peter
P
Department of Nephrology and Intensive Care, Charité Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany. peter.nickel@charite.de
Bold
Gantuja
G
Presber
Franziska
F
Biti
Didier
D
Babel
Nina
N
Kreutzer
Stephanie
S
Pratschke
Johann
J
Schönemann
Constanze
C
Kern
Florian
F
Volk
Hans-Dieter
HD
Reinke
Petra
P
D000328:Adult; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000097:blood / Q000276:immunology*; D005260:Female; D005919:Glomerular Filtration Rate / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D007518:Isoantibodies / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014184:Transplantation, Homologous; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism
C088645:IE1 protein, cytomegalovirus; D017874:Immediate-Early Proteins; D007518:Isoantibodies; D010455:Peptides; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D007371:Interferon-gamma