Candida albicans mannan-specific, delayed hypersensitivity down-regulatory CD8+ cells are genetically restricted effectors and their production requires CD4 and I-A expression.

There is considerable controversy over the induction and activity of down-regulatory cells active in various antigen-specific and antigen-nonspecific systems. We have been studying the nature of such cells in a Candida albicans mannan (MAN)-specific system for some time and report here the requirements for CD4+ and I-A+ cells during the inductive phase for the development of CD8+ effector cells, as well as the requirement for genetic compatibility for effector activity of CD8+ cells. Since we have shown previously that CD8+ down-regulatory cells were present in spleens of MAN-treated mice 4 days following the administration of MAN to naive mice, as determined by their ability to suppress delayed hypersensitivity (DH) when transferred to immunized recipients, we treated mice with monoclonal antibodies specific for CD4 and I-A at various times before, with or after the administration of MAN to assess the role of CD4+ and I-A+ cells in the development of the CD8+ effector cell. Both anti-CD4 and anti-I-A given before or up to 30 h after the administration of MAN abrogated the ability of splenocytes from MAN-treated mice to down-regulate MAN-specific DH in immunized recipients. Moreover, transfers of down-regulatory cells between H-2-incompatible strains of mice, specifically CBA/J and BALB/cByJ, provided evidence that the effector cell for the down-regulatory activity was also restricted genetically in its activity. Taken together, the data presented indicate that genetically compatible cells are required for both the inductive and effector stages of down-regulation of MAN-specific DH, suggesting that cell-cell cooperation is required for both stages and that CD4+ cells are required in a pathway leading to the development of the CD8+ effector cell.