title: Viral-induced CD28 loss evokes costimulation independent alloimmunity.
abstract: BACKGROUND
  Belatacept, a B7-specific fusion protein, blocks CD28-B7 costimulation and prevents kidney allograft rejection. However, it is ineffective in a sizable minority of patients. Although T-cell receptor and CD28 engagement are known to initiate T-cell activation, many human antigen-experienced T-cells lose CD28, and can be activated independent of CD28 signals. We posit that these cells are central drivers of costimulation blockade resistant rejection (CoBRR) and propose that CoBRR might relate to an accumulation of CD28(-) T-cells resulting from viral antigen exposure.
  
  
  METHODS
  We infected C57BL/6 mice with polyomavirus (a BK virus analog), murine cytomegalovirus (a human cytomegalovirus analog), and gammaherpesvirus (HV68; an Epstein-Barr virus analog) and assessed for CD28 expression relative to mock infection controls. We then used mixed lymphocyte reaction (MLR) assays to assess the alloreactive response of these mice against major histocompatibility complex-mismatched cells.
  
  
  RESULTS
  We demonstrated that infection with polyomavirus, murine CMV, and HV68 can induce CD28 downregulation in mice. We showed that these analogs of clinically relevant human viruses enable lymphocytes from infected mice to launch an anamnestic, costimulation blockade resistant, alloreactive response against major histocompatibility complex-mismatched cells without prior alloantigen exposure. Further analysis revealed that gammherpesvirus-induced oligoclonal T-cell expansion is required for the increased alloreactivity.
  
  
  CONCLUSIONS
  Virus exposure results in reduced T-cell expression of CD28, the target of costimulation blockade therapy. These viruses also contribute to increased alloreactivity. Thus, CD28 downregulation after viral infection may play a seminal role in driving CoBRR.
authors: Department of Surgery, Emory University, Atlanta, Georgia. Electronic address: dmou3@emory.edu.
authors: Danny
authors: D
authors: Mou
authors: Department of Surgery, Emory University, Atlanta, Georgia.
authors: Jaclyn E
authors: JE
authors: Espinosa
authors: Department of Surgery, Emory University, Atlanta, Georgia.
authors: Linda
authors: L
authors: Stempora
authors: Department of Surgery, Emory University, Atlanta, Georgia.
authors: Neal N
authors: NN
authors: Iwakoshi
authors: Department of Surgery, Duke University, Durham, North Carolina.
authors: Allan D
authors: AD
authors: Kirk
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus; D011120:Polyomavirus; D014181:Transplantation Immunology; D014777:Virus Diseases / Q000276:immunology* / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D007371:Interferon-gamma
keywords: Alloimmunity; BK; Belatacept; CD28; CMV; HV68