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Blood, 15 March 2007, Vol. 109, No. 6, pp. 2273-2274.
Bruton tyrosine kinase (Btk): key for signaling via Toll-like receptor 81 CHILDREN'S HOSPITAL BOSTON/HARVARD MEDICAL SCHOOL
The contribution of Btk to innate immune responses of myeloid cells is poorly understood. In this issue of Blood, Sochorova and colleagues demonstrate that deficient Btk function selectively impairs dendritic cell cytokine induction in response to viral single-stranded RNAs that activate Toll-like receptor 8 (TLR-8).
Btk is also expressed by non-B cells, including myeloid cells, but its roles and contributions in this context are less clear. The recent characterization of the Toll-like receptor (TLR) family of transmembrane proteins that contribute to microbial recognition is a major breakthrough in our understanding of innate immunity3,4 and represents an opportunity to better define the roles of Btk in innate responses of myeloid cells. In the report by Sochorova and colleagues in this issue of Blood, the authors studied TLR-mediated responses of monocyte-derived dendritic cells (DCs) from patients with XLA compared with adult controls. Although responses to diverse agonists of TLRs 2 through 5 were normal, TNF- From the standpoint of TLR-mediated cell activation, Sochorova et al have helped us delineate novel and distinct aspects of TLR-8–mediated signaling (see figure). Importantly, Btk has been shown to directly interact with the intracellular domain of TLR-8.7 It has also been recently demonstrated that TLR-8 agonists induce especially robust responses from human monocytes and DCs, including those derived from newborns that generally show impaired responses to many other stimuli.8 Taken as a whole, these studies suggest distinct pathways by which TLR-8 activates cells and position TLR-8 agonists as robust immune adjuvants.
From a clinical perspective, it is notable that patients with XLA have a profound susceptibility to infection with Enteroviruses that contain ssRNAs, including echoviruses, Coxsackie viruses, and polioviruses.9 Thus, the study by Sochorova et al raises the possibility that impaired TLR-8–mediated signaling in DCs of patients with XLA may contribute to their susceptibility to Enteroviruses.
Much remains to be defined with respect to the roles of Btk in TLR signaling, a challenging but worthwhile task that is being pursued in cell culture lines and primary cells. Btk mediates TLR-4–induced phosphorylation of the TLR adaptor molecule Mal in THP-1 cells10 and contributes to TLR-2– and TLR-4–induced TNF-
Footnotes
The author declares no conflicting financial interests.
REFERENCES
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
-globulin peak in the serum of a boy with recurrent infections, thereby describing an index case of X-linked agammaglobulinemia (XLA). Recombinant DNA techniques allowed for the identification of the gene defect in XLA patients leading to impaired function of the cytoplasmic tyrosine kinase named Bruton tyrosine kinase (Btk),
and IL-6 responses to ssRNAs that activate via TLR-8 were markedly impaired. Treatment of normal DCs with the Btk-selective inhibitor LFM-A13 mimicked the phenotype of XLA cells, demonstrating selective impairment in TLR-8–mediated TNF-
