MICE TRANSGENIC FOR A SOLUBLE FORM OF MURINE CTLA-4 SHOW ENHANCED EXPANSION OF ANTIGEN-SPECIFIC CD4(-CELLS AND DEFECTIVE ANTIBODY-PRODUCTION IN-VIVO() T)

CD4(+) T cell responses were analyzed in transgenic mice expressing a soluble form of murine CTLA-4, mCTLA4-H gamma 1, which blocks the inte raction of the T cell activation molecules CD28 and CTLA-4 with their costimulatory ligands. Consistent with previous reports (Linsley, P. S ., P. M. Wallace, J. Johnson, M. G. Gibson, J. L. Greene, J. A. Ledbet ter, C. Singh, and M. A. Tepper. 1992. Science (Wash. DC), 257:792), T cell-dependent antibody production was profoundly inhibited in mCTLA4 -H gamma 1 transgenic mice immunized with a protein antigen. Surprisin gly, however, transgenic mice could generate quantitatively and qualit atively normal primary T cell responses, as measured by limiting dilut ion assays and lymphokine production. In addition, in vivo expansion o f antigen-specific T cells after secondary or tertiary immunization wa s enhanced in mCTLA4-H gamma 1 transgenics as compared with normal mic e. Although unable to deliver cognate help to B cells in vivo, T cells from mCTLA4-H gamma 1 transgenic mice were not anergic as they could help B cells to produce specific antibodies when adoptively transferre d into nude hosts. Taken together, these data suggest that the engagem ent of CD28 and/or CTLA-4 may not be required for, the induction of T cell responses, as is currently understood, but rather for the express ion of T cell effector function such as the delivery of T cell help to B cells.