The homeostasis of adaptive immune responses is determined by the integrity of postreceptor signaling in its two main cellular components: T and B cells. The last 2 decades have brought up mounting information on the different intracellular routes triggered by receptor binding in T and B cells, with the identification of key signaling molecules and their genes. Today we understand better the role of different signaling molecules that drive intrathymic differentiation and postthymic function of immune cells and we are identifying the defects underlying the triggering and perpetuation of autoimmune responses. Tolerance to autoantigens depends predominantly on negative selection of autoreactive cells in the thymus and the neutralization of a small, but pathogenetically significant, surviving population of self-reactive T and B cells. There is no evidence of abnormal thymic negative selection as the basis for human systemic autoimmune diseases. Therefore, autoimmunity develops by the failure of downregulatory mechanisms needed to check activation of autoreactive cells. The mechanisms checking postthymic autoreactive cells are tolerization to self-Antigens, deletion by apoptosis, and peripheral restriction by regulatory CD4?CD25cells. In most autoimmune diseases, abnormalities of these mechanisms combine to a different degree. For example, in systemic lupus erythematosus (SLE), diminished numbers of CD4?CD25cells (Liu et al., 2004), increased apoptosis (Emlen et al., 1994), and loss of tolerance to nucleosomes (Datta, 2003) probably all contribute to a variable extent. In recent years the importance of regulated postmembrane cell signaling in the maintenance of immune homeostasis has become evident. Some biological processes are closely related to autoimmunity, among them apoptosis, a complex set of biochemical events executed by diverse signaling routes and needed to delete autoreactive cells. Faulty regulation of apoptosis and defective cytokine expression have been proposed as pathogenetic mechanisms in SLE and both mechanisms may be intertwined. Thus, antiapoptotic cytokine signaling may influence the deregulation of cell death in lupus lymphocytes since IL-2, IL-4, IL-7, and IL-15 are known to induce a pronounced increment of Bcl-2 and a concomitant reduction of T cell death (Graninger et al., 2000). Also, abnormal assembly of the T cell receptor (TCR)/CD3 complex in lupus T cells, due to diminished expression of chains (Liossis et al., 1998; Brundula et al., 1999), may alter the routes needed for regulated apoptosis (Combadière et al., 1996) and normal interleukin 2 (IL-2) production (Solomou et al., 2001). Combined genetic defects and abnormal metabolic processing may alter the configuration of the signaling cascade and favor the development of autoimmune responses. In Figure 18.1 we show a composite of mechanisms involving defective signaling in T cells that may potentially contribute to generation of sustained autoimmune responses. © 2005 Springer Science+Business Media, Inc.