ANTIGEN ORGANIZATION REGULATES CLUSTER FORMATION AND INDUCTION OF CYTOTOXIC T-LYMPHOCYTES BY HELPER T-CELL SUBSETS

Generation of effector cytotoxic T lymphocytes (CTLs) is a process tig htly governed by regulatory helper T (Th) cells. The nature of cellula r interactions as well as the precise role of distinct Th cell subsets involved in efficient CTL activation remains elusive. Employing in vi tro cultures for primary induction of human, peptide-specific CTL, a s trict requirement for Th cells and linkage of epitopes for helper and CTLs on the surface of antigen presenting cells was found, suggesting a three cell type cluster as minimal immune regulatory entity. Cognate and antigen-drivers interactions of T cells were neither essential no r sufficient to override the need for linked epitopes. Within the thre e cell type cluster complex, keyhole limpit hemocyanin or tetanus toxo id-reactive Th cells promoted generation of MAGE-3- or HIV-gag-specifi c CTL. Both type 1 and type 2 Th cells were recruited and induced by C TL. Interleukin 2 and interferon gamma were essential in early stages, and interleukin 4 was utilized in later stages, of CTL maturation. Sy nergistic effects of CD45RA(+) and CD45RO(+) Th cells were found. The data reported here suggest a critical link between the innate and adap tive immune system in the initiation process of cytolytic immune respo nses and offers the basis for efficient vaccine strategies.