Regulation of Responses to T - Independent Type 2 Antigens

Regulation of the immune response by genes located in the major histocompatibility complex (MHC) a has been extensively investigated (1-5). As a result of these studies, it has been concluded that the Ir genes of the M H C code for cell surface structures termed Ia antigens. Recognition of appropriate Ia determinants on antigen-presenting cells by Ly-1 + T cells is required for successful induction of the response (6-9). While the mechanisms of Ir gene control are poorly understood, it is clear that regulation at the level of the macrophage and at the level of the appropriate T cell are both critical (10-11). Current understanding of immune response regulation has been derived largely from studies using T-dependent antigens. Indeed, it could be postulated that Tindependent (TI) antigens would not demonstrate the same degree of specificity or Ir gene regulation. Recent evidence, however, suggests that even traditional T I antigens require at least some T cells (12-13) to produce an opt imum response. In an effort to investigate the role of Ir genes and their products in the response to T I antigens, we have analyzed the genetic restriction of the response to the TI-2 antigen 2,4,6-trinitrophenyl (TNP)-Ficoll. TNP-Ficoll, a prototypic TI-2 antigen, requires Ia + macrophages (14), a specific subset of B cells (Lyb-5 +) (15), and elicits a response in congenitally athymic mice (16). The response of nu /nu mice to TI-2 antigens suggested that T cells were not required for specific antibody production. However, rigorous depletion o f T cells from spleen cell cultures abrogated the response to TNP-Ficoll which was in turn restored by the addition of small numbers of purified T cells (12-13). These observations indicated that the response to TNP-Ficoll required T cells, although not to the extent necessary to generate a response to a T-dependent antigen. We have extended these studies to demonstrate that the in vitro antibody response to TNP-Ficoll is under strict Ir gene control. This control mapped to two complementing loci, one located in or to the left of the I-A subregion and another to the right of the I-E subregion. In addition, the response to two structurally different polysaccharides, TNP-dextran and TNP-mannan , followed the same pattern of restriction. Finally, experiments demonstrated blocking of macrophage presentation of TNP-