CD38 unresponsiveness of xid B cells implicates Bruton's tyrosine kinase (btk) as a regulator of CD38 induced signal transduction

Abstract

CD38 is a 42 kDa membrane-associated ectoenzyme expressed by a large proportion 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 accessory cells or sub-mitogenic doses of endotoxin. We show here that B lymphocytes from unstimulated X-linked immunodeficient (xid) mice are unresponsive to CD38 stimulation, both in terms of proliferative response and surface antigen modulation. This CD38 unresponsiveness is evident in the presence of excess quantities of, and normal responses to, the accessory growth co-stimulants required for this response. CD38 molecules expressed on xid B cells are normal in terms of expression levels, size and enzymatic activity, suggesting that CD38 unresponsiveness reflects a down-stream signaling defect. In light of the recent proposal that the xid gene encodes a tyrosine kinase called Bruton's tyrosine kinase (btk), these data suggest that btk is either an integral component or an indirect regulator of the CD38-induced signal transduction pathway.

B Cell Memory in xid Mice is Long‐Lived Despite Reduced Memory B Cell Frequency

“…Thus, activation and normal expansion of memory B cells seems independent of Btk. An example of Btk independent signalling is stimulation through CD40 since naive B cells from xid mice proliferate normally in response to CD40L [8,24]. If expansion and differentiation of memory B cells were to depend more on stimulation by CD40L than on pathways using Btk, such as B-cell receptor stimulation [25], then the kinetics and magnitude of the secondary response in xid mice may well be similar to that in wild type.…”

Constitutive membrane association potentiates activation of Bruton tyrosine kinase

“…These diseases are characterized by defects in B cell development and function. Genetic and biochemical analyses indicate that Btk is a component of the signal transduction pathways utilized by the B cell antigen receptor (BCR), IL-5R, IL-6R, IL-10R, CD38, and FceRI (Wicker and Scher, 1986;Hinshelwood et al, 1995;Saouf et al, 1994;Aoki et al, 1994;de Weers et al, 1994;Koike et al, 1995;Sato et al, 1994;Hitoshi et al, 1993;Matsuda et al, 1995;Santos-Argumedo et al, 1995;Go et al, 1990;Kawakami et al, 1994). Activation of Btk by either receptor crosslinking or a point mutation E41K in the PH domain (Btk*) is dependent on Src family kinases Afar et al, 1996;Saouf et al, 1994;Mahajan et al, 1995) and is correlated with increased tyrosine phosphorylation Li et al, 1995;Mahajan et al, 1995;Hinshelwood et al, 1995;Aoki et al, 1994;de Weers et al, 1994;Saouf et al, 1994;Sato et al, 1994;Kawakami et al, 1994;Matsuda et al, 1995) and translocation to the plasma membrane (Li et al, 1995;Kawakami et al, 1994).…”

In situdetection of activated Bruton’s tyrosine kinase in the Ig signaling complex by phosphopeptide-specific monoclonal antibodies

“…XLA manifests as a severe humoral immunodeficiency with an absence of functional B cells in the periphery. xid results in an alteration of normal B cell development that reduces the total peripheral B cell population by Ϸ50% and impairs functional responses to certain T cell-independent antigens, activation of the BCR, interleukin-5 receptor, interleukin-10 receptor, CD38, and CD40 on B cells; the Fc ⑀ receptor on mast cells; and non-integrin collagen receptors on platelets (7)(8)(9)(10)(11)(12)(13)(14)(15). Transgenic model systems demonstrate a Btk dose-dependent phenotype of immunodeficiency and B cell dysfunction in vivo (16).…”