Simplistically, one may view the immune system as a war machine consisting of numerous lymphocytes, each with a. specific surface receptor for antigen, designed to protect the integrity of the organism. Antigen-inexperienced lymphocytes patrol the body as quiescent cells unless selected by antigen to divide and become effector cells. Different lineages of lymphocytes engage in different effector functions, like secretion of large amounts of antigenspecific molecules, named antibodies, by B cells; destruction of virus-infected cells by cytotoxic T cells; or secretion of hormone-like lymphokines by T helper cells, which support antibody production by B cells or expansion of cytotoxic T cells. The T killer cell receptor is not secreted and b’inds to peptides mostly derived from intracellularly produced proteins, such asviral proteins, that are transported to and presented on the cell surface by peptide-binding major histocompatibility complex (MHC)-encoded molecules (Bjorkman et al., 1987). The receptor of T helper cells can bind to peptides that are derived from internalized proteins as well as other proteins entering the endocytic route and presented by class II MHC molecules. The binding of the T cell receptor (TCR) to MHC-antigen is assisted by CD4 and CD8 coreceptors on the surface of T helper and T killer cells, respectively. The CD4 coreceptor binds to class II and the CD8 coreceptor to class I MHC molecules. Coengagement of TCR and coreceptor by the same MHC molecules generates cell-activating signals that are transmitted by the TCR-associated CD3 y, 6, E,<, or q proteins (Weiss and Littman, 1994 [this issue of Cell]), while ligand binding by the immunoglobulin receptor on B cells generates signals transduced by the immunoglobulinassociated a and p proteins (Reth et al., 1991)(Figure 1). In mammals, lymphocytes as well as their antigen receptors are formed de novo throughout life in primary lymph organs, like the T cell-producing thymus or the B cellproducing bone marrow, that are colonized by lymphopoietic precursor cells. The antigen-receptor genes are formed in immature lymphocytes by rearrangement of V (variable), D (diversity), J (joining), and C (constant) gene segments (Tonegawa, 1983), resulting in productive genes that encode either the disulfide-linked heavy and light chains of the immunoglobulin receptor on B cells or the disulfide-linked a and 0 TCR proteins.(The~ 6 TCRs of other lymphocytes are not discussed here becauseof their largely unknown function.) The newly formed lymphocytes will then migrate from the primary lymph organ and enter the secondary lymph compartments via the blood or lymphatic vessels.

Because of the by and large stochastic nature of antigen-receptor formation, there will not only be receptors for foreign but also for the self-components of the organism. Therefore, there must be some form of “negative” selection that prevents self-specific lymphocytes from becoming autoaggressive (see Nossal, 1994 [this issue of Cell]). It was argued that, in addition to negative selection, there is also positive selection of lymphocytes by internal ligands that serves the purpose of avoiding the accumulation of useless lymphocytes with either no receptors at all or with receptors that are useless for the organism. For instance, it was proposed that there is positive selection of lymphocytes that are especially effective in recognizing foreign peptides presented by self-MHC molecules. When discussing selection of lymphocytes by self-or internal ligands, we find that the analogy between the immune system and a war machine is no longer useful. In fact, a much more complex view of the immune system was propagated …