We have transfected the mouse CD4 gene into a beef insulin (BI)-specific murine T helper hybridoma that lacks CD4 surface expression. The CD4-expressing transfectants have acquired an additional reactivity for pork insulin (PI), which was not detectable in the original recipient cell. The transfectants' response to PI can be completely abrogated by anti-CD4 antibodies. The transfected clone showed a 50-fold increased sensitivity towards BI in comparison to the same CD4- hybridoma. These experiments suggest that CD4 may be important in determining the antigen fine specificity and, therefore, may also play a role in altering the T cell repertoire.