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THE COUNCIL FOR TOBACCO RESEARCH-U.S.t1., INC. 900 THIRD AVENUE NEW YORK. N.Y. 10022 Menorandum To:. Dr. H.McAllister and Staff Fran: D.H.Ford Re: Site visit with Dr. Victor Enge]hard, University of Virginia, Charlottesville, Oct. 13, 1993. Grant No. 3229R2 entitled "T-cell respazses to hlman class II PgiC molecules in human CD4 transgenic mice." Goals : Brief ly : To understand the reasons for the unique f ocus of T ce l ls on the MHC proteins as recognition elements, and to understand the role that the CD4 coreceptor plays in the reco:3rLitiaz of MHC class II molecules. Progress: It appears that a cansiderable aarwunt of progress has been made, despite aviral infection in his breeding colony. This lead to what appeared to be spurious results, which Dr. Engelhard believes he has accounted for as well as correcting the infection in his colony. His hypothesis is that the expression of human CD4 in transgenic mice will modify the magnitude of T cell responses to human class II molecules via a species-specific interaction. Results: 1. Hutnan CD4 molecules expressed in transgenic mice function in signal transducticn events (antibody synergism). 2.Hianan CD4 preferentially augmented responses to human, as opposed to murine class II molecules. 3. Both allogenic and xeno3enic responses were con&ll,ed entirely by human CD4, while the murixve CD4 was functionally inactive (antibody blocking), indicating that human CD4 interacts with murine as well as human class II molecules. 4. Hccaever, the level of response to human class II molecules was far below the level of response to murine clAss II a1lDantigens. In other studies his results indicate: that coexpressicn of both human CD4 and human class II molecules augment the positive selection of human class II specific cells in transgenic mice. Responses to human class II molecules on lymphoblastoid cell lines approached those for allogenic responses. Responses to DQ3.2 class II molecules expressed on murine sleen cells did not reach the level of a typical allogenic response. He feels this may in part reflect a poor stimulatory capacity of DQ class II molecules as compared to DR class molecules. In another study, transgenic mice which. expressed human CD4• in both murine CD4+ and CD8+ T cell subsets were evaluated to determine if human CD4 in the murine CD8+ cells would confer a specificity for MHC class II molecules. It was then cbserved that the CD8+ T cells from human CD4 transgenic mice responded st^tngly to class II alloantigens (Ixn1.2) while cells from normal littermates did not. This response was blocked by anti-human CD4 antibodies while antibodies to murine CD8 had little effect. Finally, Dr. Ehgelhard concludes that: Expression of human CD4 in a murine CD8 subset of T cells conferred a specificty for class II m:lecules and a dimin- ished repcnse for class I. This might reflect a ccmpetition between hunian CD4 and murine CD8 for factors involved in T cell activation, such as by p561ck, This suggests that this corecptcr molecule may be important in antigen recog- nition and T cell signalling. Cccnnent: An interesting well organized program directed by an enthusiastic lmawledgable investigator which appears likely to expand our understanding of the roles these molecules play in imnunalogy. DHF