Immunologic 'ignorance' of vascularized organ transplants in the absence of secondary lymphoid tissue.

Secondary lymphoid organs (the spleen, lymph nodes and mucosal lymphoid tissues) provide the proper environment for antigen-presenting cells to interact with and activate naive T and B lymphocytes. Although it is generally accepted that secondary lymphoid organs are essential for initiating immune responses to microbial antigens and to skin allografts, the prevailing view has been that the immune response to primarily vascularized organ transplants such as hearts and kidneys does not require the presence of secondary lymphoid tissue. The assumption has been that the immune response to such organs is initiated in the graft itself when recipient lymphocytes encounter foreign histocompatibility antigens presented by the graft's endothelial cells. In contrast to this view, we show here that cardiac allografts are accepted indefinitely in recipient mice that lack secondary lymphoid tissue, indicating that the alloimmune response to a vascularized organ transplant cannot be initiated in the graft itself. Moreover, we demonstrate that the permanent acceptance of these grafts is not due to tolerance but is because of immunologic 'ignorance'.

The alloimmune response and effector mechanisms of allograft rejection.

Allograft rejection is the consequence of the recipient's alloimmune response to nonself antigens expressed by donor tissues. Allospecific T lymphocytes are activated by donor peptides which are presented in the context of major histocompatibility complex molecules by either donor or recipient antigen presenting cells. Antigen presenting cells also provide essential costimulatory signals which are required for T cell proliferation and differentiation into either helper or effector lymphocytes. Effector mechanisms of allograft rejection include those mediated by cytotoxic T lymphocytes, macrophages, natural killer cells, and B lymphocytes. Importantly, alloimmune responses are controlled by regulatory molecules which include membrane receptors and cytokines. Novel insights into the interactions between antigen presenting cells and T lymphocytes, and further understanding of how alloimmune responses are regulated, will help in developing effective antirejection and tolerance-inducing strategies.

The role of the common cytokine receptor gamma-chain in regulating IL-2-dependent, activation-induced CD8+ T cell death.

IL-2-dependent, activation-induced T cell death (AICD) plays an important role in peripheral tolerance. Using CD8+ TCR-transgenic lymphocytes (2C), we investigated the mechanisms by which IL-2 prepares CD8+ T cells for AICD. We found that both Fas and TNFR death pathways mediate the AICD of 2C cells. Neutralizing IL-2, IL-2R alpha, or IL-2R beta inhibited AICD. In contrast, blocking the common cytokine receptor gamma-chain (gamma c) prevented Bcl-2 induction and augmented AICD. IL-2 up-regulated Fas ligand (FasL) and down-regulated gamma c expression on activated 2C cells in vitro and in vivo. Adult IL-2 gene-knockout mice displayed exaggerated gamma c expression on their CD8+, but not on their CD4+, T cells. IL-4, IL-7, and IL-15, which do not promote AICD, did not influence FasL or gamma c expression. These data provide evidence that IL-2 prepares CD8+ T lymphocytes for AICD by at least two mechanisms: 1) by up-regulating a pro-apoptotic molecule, FasL, and 2) by down-regulating a survival molecule, gamma c.