The double cascade of lymphoid proliferation: Current challenges and problem areas

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Abstract
Two largely but not entirely separate cascades of proliferation and differentiation are involved in immunity. First, processes that are mainly independent of the entry of antigen into the body generate the two types of lymphocytes, T cells and B cells. This lymphoneogenesis proceeds in the thymus and the bone marrow, respectively. It creates families and subfamilies of nondividing cells that do nothing but patrol the body until antigen enters. Each lymphocyte set represents a repertoire of recognition units preequipped with receptors for antigen, and each individual lymphocyte carries its own particular specificity as a result of a somatic rearrangement of genes. When an antigenic stimulus is given, the second and antigen‐dependent wave of proliferation and differentiation occurs. This involves clonal selection of particular lymphocytes within the repertoire with specificity for the antigen, and the generation of both immunologic effector cells and memory cells. This second cellular cascade takes place chiefly in the secondary lymphoid tissues, e.g., lymph nodes or spleen. The developing immune system learns to discriminate self from not‐self. The paper outlines the chief mechanisms operative in immunologic tolerance and also briefly addresses the fact that T lymphocytes must learn to “see” antigens in association with a “self” major‐histocompatibility‐complex antigen. Both proliferative cascades depend on intercellular interactions, but much more is known about those operative in antigen‐driven lymphocyte activation. Here there is a cyclical process in which antigen‐trapping cells stimulate helper/inducer T cells, which in turn stimulate cytotoxic/suppressor T cells or B cells. Some T‐cell products can augment the antigen‐trapping cells' inductive role. The structure of some of the molecules involved is rapidly being revealed by gene cloning and expression, but the anatomic basis of cell interactions within the lymphoid system is not being addressed as fully as it might be.