Grant: Discovery Grants Program - Individual

Immune systems respond to fight foreign invaders and yet do not respond to "self" cells or molecules. This attribute of the immune system is referred to as self-nonself discrimination. There are two recognized mechanisms by which the ability to respond against self antigens is ablated. Firstly, lymphocytes with receptors that bind to self-antigens are ablated on interacting with the antigen when first generated in the organs supporting lymphocyte development. Some "peripheral" self-antigens are insufficiently present in such organs to ablate their corresponding lymphocytes. Thus the pool of mature lymphocytes, that circulates via the blood and traffics through the spleen and lymph nodes, contains some lymphocytes specific for these peripheral self antigens. The inappropriate activation of these lymphocytes can result in autoimmunity. Mature lymphocytes can be inactivated (the second mechanism of ablation) or activated by antigen, the latter process resulting in the cells that mediate immune responses, for example antibody producing cells. There are three classes of lymphocytes. The activation of B cells gives rise to cells that produce antibody; of "CD8 T lymphocytes" to cytotoxic T lymphocytes (CTL) that kill virally-infected or cancer cells; and of CD4 T lymphocytes to T helper (Th) cells that allow antigen to facilitate or help in the activation of B and CD8 cells. We proposed in 1970 that a single lymphocyte interacting with antigen would be inactivated, whereas the activation of a target lymphocyte required its antigen-mediated interaction with antigen-specific Th cells, providing a mechanism by which lymphocytes specific for peripheral self-antigens could be ablated and lymphocytes specific for foreign antigens activated. This idea was supported by the subsequent findings that Th cells are required for antigen to activate B and CD8 T cells, and their inactivation by antigen in the absence of Th cells. The studies proposed will test a detailed hypothesis for how antigen interacts differently with CD4 T cells to activate or inactivate them. This hypothesis incorporates the idea that a single target CD4 T will be inactivated by antigen, whereas its activation requires help from another CD4 T cell, i.e. requires CD4 T cell cooperation. Our hypothesis is contrary to the ideas most immunologists currently hold. We argue it is both better supported by observation and is physiologically more plausible. Moreover, all agree that the different circumstances leading to the antigen-dependent activation or inactivation of CD4 T cells is a most critical question, as it appears that such activation is required to initiate almost all adaptive immune responses. Thus an understanding of these circumstances is required to envisage how autoimmunity to peripheral self antigens can occur and how the strength of immune responses can be facilitated by increasing the effective activation of CD4 T cells.