Ignorance is bliss

In an elegant transgenic mouse model, Bolinger and colleagues provide evidence that endothelial cells expressing a nonself minor histocompatibility antigen neither activate nor tolerize CD8⁺ T cells. Instead, the antigen is ignored by the immune system. The findings are relevant to both graft-versus-host disease and the rejection of solid-organ transplants.

Biologists are notoriously preoccupied with how and why things happen. “How” questions address the mechanisms by which a biological or disease process comes about. “Why” questions query the evolutionary origins of the process under investigation. However, like good detectives, biologists must first define where a given process is initiated. Without knowing the “where” of things, it would be quite difficult, if not impossible, to unfold the answers to “how” and “why” questions.

In the current issue of Blood, Bolinger et al follow up on an important but still controversial “where” question in transplantation immunology: can immunity toward, or tolerance of, a histocompatibility antigen arise outside lymphoid tissues? Specifically, they ask whether endothelial cells, the first cells encountered by hostile lymphocytes in either graft-versus-host disease or solid-organ transplants, are capable of presenting antigen and initiating immunological events. To answer this question, they analyze the in vivo CD8⁺ T-cell response to a nonself minor histocompatibility model antigen (β-galactosidase) whose expression is transgenically restricted to the endothelium. They provide compelling evidence that antigen-specific CD8⁺ T cells are neither activated nor tolerized by endothelial cells bearing the antigen. In fact, β-galactosidase–specific CD8⁺ T cells in this system could be activated only when cross-primed by dendritic cells. Dendritic cells, unlike endothelial cells, are professional antigen-presenting cells that readily migrate to lymphoid tissues. Likewise, they show that peripheral immunological tolerance to the β-galactosidase antigen is dependent on encountering the antigen within the bone marrow. The findings therefore imply that nonself antigens that remain outside lymphoid tissues lead to neither immune activation nor tolerance. Instead, they are blissfully ignored by the immune system.

The concept of immunological ignorance and the central role of antigen location in shaping immunity are best supported by landmark experiments performed by Zinkernagel and colleagues. The Zinkernagel group has repeatedly shown that viral, tumor, or tissue antigens that do not gain access to secondary lymphoid tissues do not initiate primary immune responses.¹  Although the same appeared to be true for vascularized organ transplants,²  the view that alloimmune responses are not initiated at the organ's endothelial-cell lining (but instead in organized secondary lymphoid tissues by migrating, antigen-bearing cells) was quickly challenged. Evidence was provided that endothelial cells present antigen and activate CD8⁺ T cells under certain in vitro or in vivo conditions.³  But one cannot be certain whether, in these experiments, antigen presentation was restricted to endothelial cells. The report by Bolinger et al goes one step further by transgenically fixing the expression of the foreign antigen on endothelial cells to demonstrate with reasonable certainty that endothelial cells are not sufficient for primary T-cell activation. The Bolinger report, however, would have been more complete if, in the critical experiments whereby β-galactosidase transgenic organs were transplanted into wildtype recipients, graft survival was followed over a longer period of time and the absence of chronic rejection (graft vasculopathy) was ruled out by histological examination.

The dictum that alloimmune responses are initiated within lymphoid tissues and not in the periphery is germane to the clinical practice of both solid-organ and hematopoietic stem cell transplantation. As inflammation subsides after the transplantation procedure, reduced traffic of donor antigens to lymphoid tissues and thus, diminished naive T-cell activation, ensures that less immunosuppression is required over time to prevent organ rejec-tion and graft-versus-host disease. Stated differently, a small but blissful dose of immunological ignorance is quietly helping transplant recipients live long and healthy lives.