CANDIDA-ALBICANS MANNAN-SPECIFIC, DELAYED-HYPERSENSITIVITY DOWN-REGULATORY CD8-A EXPRESSION( CELLS ARE GENETICALLY RESTRICTED EFFECTORS ANDTHEIR PRODUCTION REQUIRES CD4 AND I)

There is considerable controversy over the induction and activity of d own-regulatory cells active in various antigen-specific and antigen-no nspecific systems. We have been studying the nature of such cells in a Candida albicans mannan (MAN)-specific system for some time and repor t here the requirements for CD4+ and I-A+ cells during the inductive p hase for the development of CD8+ effector cells, as well as the requir ement for genetic compatibility for effector activity of CD8+ cells. S ince we have shown previously that CD8+ down-regulatory cells were pre sent in spleens of MAN-treated mice 4 days following the administratio n of MAN to naive mice, as determined by their ability to suppress del ayed hypersensitivity (DH) when transferred to immunized recipients, w e treated mice with monoclonal antibodies specific for CD4 and I-A at various times before, with or after the administration of MAN to asses s the role of CD4+ and I-A+ cells in the development of the CD8+ effec tor 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 MA N-treated mice to down-regulate MAN-specific DH in immunized recipient s. Moreover, transfers of down-regulatory cells between H-2-incompatib le strains of mice, specifically CBA/J and BALB/cByJ, provided evidenc e that the effector cell for the down-regulatory activity was also res tricted genetically in its activity. Taken together, the data presente d 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 o f the CD8+ effector cell.