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Blood, 1 July 2008, Vol. 112, No. 1, pp. 3.
EnABLing the immune synapseTUFTS UNIVERSITY SCHOOL OF MEDICINE
In this issue of Blood, Huang and colleagues reveal new insights into the mechanism by which c-Abl protein regulates T-cell responses through actin-mediated effects on the immune synapse.
The knowledge that tyrosine phosphorylation of HS1 is required for its ability to promote actin polymerization at the IS, and that c-Abl kinase activity is important for IL-2 production,2,3 an important consequence of T-cell activation, led Huang and colleagues to explore the link between c-Abl and formation of the IS. c-Abl, the tightly regulated protein tyrosine kinase that is aberrantly expressed as a Bcr fusion in chronic myelogenous leukemia (CML), has been implicated in a wide range of cellular functions. Unlike its oncogenic Bcr/Abl counterpart, c-Abl shuttles between the cytoplasm and the nucleus and influences proliferation, survival, the DNA damage response, and other processes. However, despite the long-standing observation that the immune response is impaired in c-abl–null mice, a clear understanding of the mechanisms underlying this impairment has been slow to emerge. By using imatinib, a drug that inhibits c-Abl activity and shRNA, the authors demonstrate that c-Abl interacts with HS1 and that c-Abl kinase activity enhances HS1 phosphorylation and proper formation of the IS. Interestingly, HS1 phosphorylation by ZAP-70, another regulatory molecule that affects IS formation, is not affected by c-Abl, highlighting the importance of multiple phosphorylation steps in achieving proper regulation. Using video microscopy, the authors reveal that c-Abl affects the IS in a second way. Unlike HS1-deficient cells, in which actin-rich structures disassemble quickly, c-Abl–deficient cells were compromised in spreading and formation of lamellipodia. These defects appear to involve effects on WAVE2, which fails to localize correctly when c-Abl activity and expression are suppressed. In addition to making important contributions to our understanding of the regulation of IS formation, these experiments raise a number of intriguing questions. For example, do independent signals trigger phosphorylation of HS1 by ZAP-70 as opposed to c-Abl? Perhaps ZAP-70–mediated phosphorylation of HS1 allows the c-Abl SH2 domain to bind to HS1, thereby facilitating c-Abl–mediated phosphorylation of another residue on HS1, allowing the molecule to fully participate in IS formation. Although WAVE2 is crucial for actin polymerization and IS formation, whether c-Abl exerts its affect through direct interaction or through interaction with another component of the WAVE complex requires additional work. c-Abl deficiency also affects chemokine-induced T-cell migration, and discovering whether this phenomenon reflects effects on HS1 or WAVE2 or other molecules should provide a clearer understanding of the mechanisms involved in chemotaxis. Lastly, and perhaps most intriguingly, this work raises the possibility that complications with infection seen in imatinib-treated CML patients stem from inhibition of c-Abl and an impaired T-cell response.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
REFERENCES
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
