CD38 UNRESPONSIVENESS OF XID B-CELLS IMPLICATES BRUTON TYROSINE KINASE (BTK) AS A REGULATOR OF CD38 INDUCED SIGNAL-TRANSDUCTION

CD38 is a 42 kDa membrane-associated ectoenzyme expressed by a large p roportion of human and mouse lymphocytes. Agonistic antibodies to CD38 induce a strong proliferative response in lymphocytes additionally co -stimulated with other growth co-factors such as IL-4, IL-2 plus acces sory cells or sub-mitogenic doses of endotoxin. We show here that B ly mphocytes from unstimulated X-linked immunodeficient (xid) mice are un responsive to CD38 stimulation, both in terms of proliferative respons e and surface antigen modulation. This CD38 unresponsiveness is eviden t in the presence of excess quantities of, and normal responses to, th e accessory growth co-stimulants required for this response. CD38 mole cules expressed on xid a cells are normal in terms of expression level s, size and enzymatic activity, suggesting that CD38 unresponsiveness reflects a down-stream signaling defect. In light of the recent propos al that the xid gene encodes a tyrosine kinase called Bruton's tyrosin e kinase (btk), these data suggest that btk is either an integral comp onent or an indirect regulator of the CD38-induced signal transduction pathway.