The functional significance of multiple cells--among lymphoid and nonlymphoid cells--capable of having Ia molecules on their membranes must be critically addressed. Ia is absolutely required before a cell can interact with helper T cells, but it is not clear whether the presence of this protein is all that is needed for antigen presentation. Indeed, at present, except for the macrophage, few cells have been studied for antigen presentation using a wide range of protein antigens, either soluble or particulate. On the basis of the studies discussed in the first section, it appears that the recruitment of most helper-T cell clones takes place by APC that can internalize and process the protein antigens, be they soluble or part of the structure of microorganisms. The fact that helper T cells are programmed to recognize antigen in the context of Ia, and therefore on an APC such as the macrophage, forces recognition of antigens that are altered or processed. Indeed, proteins in their native state may not remain membrane-bound for long periods; the T cells, therefore, have the opportunity to recognize the altered fragments. To this issue is added the requirement for the T-cell receptor to interact with Ia molecules. The available information, therefore, leads one to conclude that APC deficient in their capacity to internalize and process proteins will not be able to present them. The finding that small peptides from a previous catabolism of proteins can be presented without further handling implies that APC with limited processing capacity could be involved in presentation of such small peptides. The different Ia-positive APC of the lymphoid organs may interact to different extents with protein antigens and collaborate with each other to bring about an effective stimulation of the clones of helper T cells. The macrophage, being the most ubiquitous cell and the one capable of interacting with many proteins, is our candidate as the major APC involved in the recruitment and enlargement of clones T cells. The observations that macrophages can release proteins partially altered implies that there may be cooperativity among the various APC. Data for this have been obtained. Most likely B cells will be found to have a limited capacity to present all antigens because of their inherent difficulties in internalizing large particulate materials. In such instances, B cells may interact with the solubilized proteins released by the macrophages. The same may apply to the Langerhans/dendritic cells.(ABSTRACT TRUNCATED AT 400 WORDS)