Mice transgenic for a soluble form of murine CTLA-4 show enhanced expansion of antigen-specific CD4+ T cells and defective antibody production in vivo.

CD4+ T cell responses were analyzed in transgenic mice expressing a soluble form of murine CTLA-4, mCTLA4-H gamma 1, which blocks the interaction 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. Ledbetter, 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. Surprisingly, however, transgenic mice could generate quantitatively and qualitatively normal primary T cell responses, as measured by limiting dilution assays and lymphokine production. In addition, in vivo expansion of antigen-specific T cells after secondary or tertiary immunization was enhanced in mCTLA4-H gamma 1 transgenics as compared with normal mice. 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 transferred into nude hosts. Taken together, these data suggest that the engagement 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 expression of T cell effector function such as the delivery of T cell help to B cells.