Requirement for help in the generation of alloantigen-specific helper cells

Control mechanisms that regulate the induction of T helper cells are a key component of conceptual schemes to understand the network of interactions controlling the immune response. In this work, using a sequential three-step culture system, we demonstrate that the generation of the T helper cells that participate in cytotoxic T cell induction is itself dependent on interactions with helper cells. The induction of Ly7- pre-Th requires collaboration with a Th-directed Ly1+7+ helper T cell with radioresistant function and the participation of an adherent cell. Th have been generated from thymic responders and from anti-Ly7-treated splenic responders, both of which are deficient in Th effector function. Approximately 10-30-fold more help is generated from splenic as compared with thymic pre-Th. Ly7+ Th were required throughout the first 5 days of CTL generation. Using a limiting dilution analysis of pre-Th we have shown that splenic precursor Th are inducible with IL-2, but that the frequency of clones able to deliver antigen-specific help in a CTL response is an order of magnitude lower than the frequency of clones induced by antigen and able to secrete IL-2 reported by others. For reasons described in the discussion, we suggest that Th and IL-2 secretors may be at least partially nonoverlapping subsets. The CTL-directed Th effectors induced by IL-2 were analyzed for specificity; 65% of clones were challenge-specific, 29% were crossreactive, and 6% were heteroclitic. We conclude that the Th that participate in the induction of pre-Th coexist with, and bear markers similar to, the Th that act in the induction of pre-T suppressor cells, and of CTL. It seems possible that the control over the class of precursor induced by antigen may be a function of the quantity rather than the quality of helper effectors.