In order to more precisely define the nature and function of genes controlling the cellular interactions involved in the antibody response and/or Ir genes controlling response to certain soluble antigens, an in vitro system for generating both primary and secondary antibody responses to soluble antigens has been developed and characterized. Responses in the system are T-cell and accessory cell dependent, and for TNP-(T,G)-A--L and TNP-(H,G)-A--L are clearly under H-2 linked Ir gene control. The function of accessory cells in response to TNP-(T,G)-A--L and TNP-(H,G)-A--L is also regulated by H-2 linked Ir genes encoded within the same subregions of H-2 as the overall in vitro and in vivo responses to these antigens. In addition, it has been found that the generation of specific antibody responses to antigen requires the active recognition by T-cells of H-2 antigens (probably Ia antigens) as "self" that are expressed by accessory cells. The H-2 antigens that are in fact recognized as "self" are not determined by the genotype of the T cells, but rather are determined by the genotype of the thymus in which the T-cells matured.