B LYMPHOCYTES are key participants in the immune response because of their specificity, their ability to take up and present antigens to T cells, and their capacity to differentiate into antibody-secreting cells. To limit reactivity to self antigens, autospecific B cells can be functionally inactivated or deleted. Developing B cells that react with membrane antigens expressed in the bone marrow are deleted from the peripheral lymphocyte pool. It is important to ascertain the fate of B cells that recognize membrane autoantigens expressed exclusively on peripheral tissues because B cells in the peripheral lymphoid organs are phenotypically and functionally distinct from bone-marrow B cells. Here we show that in immunoglobulin-transgenic mice, B cells specific for major histocompatibility complex class I antigen can be deleted if they encounter membrane-bound antigen at a post-bone-marrow stage of development. This deletion may be necessary to prevent organ-specific autoimmunity.

Although convincing evidence has been obtained for the imposition of self-tolerance by the intrathymic deletion of self-reactive T cells, the development of tolerance to antigens which are expressed only in the periphery is not so well understood. We have approached this question by creating transgenic mice which carry a class I major histocompatibility complex (MHC) gene (H-2Kb) linked to the rat insulin promoter. Mice expressing the transgene develop diabetes, but do not appear to mount an immune response against the transgene-expressing pancreatic beta-cells, even when the transgene is allogeneic with respect to the endogenous host H-2 antigens. We have now explored the mechanism of this tolerance further. We find that spleen cells from pre-diabetic transgenic (RIP-Kb) mice do not kill targets bearing H-2Kb, whereas thymus cells from the same mice do. The unresponsiveness of these spleen cells can be reversed in vitro by providing recombinant interleukin-2 (rIL-2). In older, diabetic mice, responsiveness develops as the pancreatic beta-cells are lost. Our results point to an extrathymic mechanism of tolerance induction, dependent on the continuous presence of antigen and the lack of IL-2 in the local environment of potentially reactive T cells.

The Ly and Ia phenotypes of T lymphocytes involved in different functions were characterized by the use of specific antisera. T cells responsible for delayed-type hypersensitivity (DTH) and for helper functions were found to be Ly-1+,2- in contrast to cytotoxic T cells and T cells responsible for suppression of antibody responses which were Ly-1-,2+. Unlike some primed helper cells, T cells involved in DTH were Ia-. Suppressor cells in the system were Ia+.