A mAb, ALP-2, produced by immunizing rats with proliferating lymph node cells from MRL/Mp-lpr/lpr mice, had an inhibitory effect on recombinant interleukin 4 (rIL-4)-mediated proliferation and differentiation of murine B cells. Kinetic analysis revealed that the ALP-2 exerted these inhibitory effects at an early phase of B cell proliferation and differentiation. Nevertheless, the proliferative response of thymocytes to rIL-4 was not inhibited by ALP-2. In addition, ALP-2 inhibited neither the B cell proliferation induced by interleukin 2 nor the B cell differentiation by interleukin 5. Cross-inhibition experiments, together with immunoblotting analysis, revealed that the LP-2 recognized by ALP-2 appears to be an epitope of CD45R (B220) molecule(s), the isoform(s) of the Ly-5 antigen system. Epitope mapping analysis using CD45 gene transfectants showed that Lp-2 epitope is dependent upon the expression of the first alternatively spliced exon of CD45 gene. Functional studies showed that the mAb to an epitope of CD45R, RA3-2C2, but not RA3-6B2, had similar inhibitory effects on the IL-4-mediated proliferative response of B cells. These findings suggest that the CD45R molecules associated with Lp-2 and RA3-2C2 epitopes are probably related to a signal transduction provided by IL-4 in B cells. The possibility that different pathways are operative for IL-4-mediated signaling between B and T cells has to be considered.