The CBA/N mouse carries the X-linked immunodeficiency rid, resulting in defective B cell development. B cells from these animals cannot mount antibody responses to type 2 T-independent antigens, and do not synthesize DNA when stimulated with anti-immunoglobulin (Ig) antibodies which are mitogenic for normal B cells. The primary antibody responses of CBA/N mice to T-dependent antigens have also been reported to be abnormal. Here we describe the results of experiments which demonstrate that the B cells from these animals respond abnormally to ligation of CD40, a B cell surface molecule now known to play a key role during T cell-B cell interactions, via its interaction with the counterligand (CD40L) expressed by activated T cells. Hence, rid B cells fail to proliferate when cultured with preactivated T helper type 2 (Th2)T cells (known to express CD40L),with a soluble CD40L-CD8 fusion protein, or in response to monoclonal antibodies to CD40, even in the presence of IL-4 and/or anti-Ig reagents. However, rid B cells do receive abortive activation signals following ligation of CD40, as manifested by up-regulation of class II major histocompatibility complex and CD23 antigens. Since the rid defect has now been identified as a point mutation in the protein tyrosine kinase Btk, our results point to an important role for this kinase in the downstream signaling cascade elicited in response to ligation of either surface Ig or CD40.
