The advent of immunosuppression has been invaluable in prolonging survival of transplanted organs. However, systemic immunosuppression renders individuals vulnerable to infections that may trigger rejection or the development of virus-mediated cancers. Understanding the mechanisms responsible for this increased rejection following viral infection is critical for defining new therapeutic strategies.

The study objective was to assess whether the increased incidence of transplant rejection is due (i) to crossreactivity of pathogen-specific T cells with alloantigens or (ii) to decreased regulation of allo-specific responses.

In a fully allogeneic skin graft model, B6 (H2Kb) recipients were adoptively transferred with TEa transgenic T cells (CD4⁺, responding to BALB/c antigen presented on IAb) prior to transplantation with BALB/c (H2Kd) skin grafts. To address the effect of pathogen infection on immune tolerance, mice were infected with murine cytomegalovirus (mCMV) at the time of transplantation. Accelerated rejection occurred in recipients with a concurrent mCMV infection compared to uninfected controls. To determine whether the increased rejection was due to increased bystander activation of alloreactive T cells, we measured the accumulation and cytokine production of CD4⁺, CD8⁺, and allo-reactive TEa T cells. Results showed that mCMV infection increased apoptosis and reduced accumulation of total CD4⁺, CD8⁺, and allo-reactive TEa T cells in draining lymph nodes (dLNs) of skin graft recipients during the acute phase of the infection. Ex vivo restimulation of CD8⁺ T cells with alloantigens revealed a high level of TNF and IFN-Γ production similar to that in uninfected animals.

Due to the reduced accumulation of cells in the dLNs, we hypothesized that the increased rejection may be due to reduced regulation of allo-responses. Upon analysis of CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Treg) in different lymphoid compartments, we determined that Treg were significantly reduced in the spleen, dLNs, and allograft. The diminished Treg numbers was further reflected by a significant increase in CD8⁺ T cell infiltration into the graft following mCMV infection compared to uninfected controls. These data reveal that increased rejection of allograft following mCMV infection is not dependent on the accumulation of crossreactive T cells, but rather a deregulation of immuno-suppressive responses.

« Back to 2013 American Transplant Congress