We will investigate the process of B-lymphocyte differentiation from stem cells to mature plasma cells, with emphasis on sequential changes in cell morphology, function, and expression of immunoglobulin class which accompany development of this cell line. Development of B lymphocytes in bone marrow of adult mice will be compared to ontogenetic development of these cells in fetal mice. In vitro culture systems in which B lymphocytes are activated by mitogens to differentiate to cells synthesizing the major immunoglobulins will be used for studies of the relationship of class of immunoglobulin on the surface of precursor B lymphocytes to the class synthesized by mature progeny. The mechanism by which antibodies to IgM block this differentiation, and the possible relationship of this mechanism to acquisition of B-cell tolerance, will be studied. The processes through which lymphocytes become restricted to synthesis of a single immunoglobulin class will be explored, together with exceptions to this rule which occur in murine myelomas and following certain types of immunization. Experiments of B-cell differentiation in animals will be integrated with studies of differentiation defects in immunodeficient patients. We will focus particularly on the defects of T lymphocytes which may lead either to active suppression or failure to cooperate in induction of B-lymphocyte differentiation.