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CD5 and B lymphocyte responses: multifaceted effects through multitudes of pathways and channels

Cellular & Molecular Immunology volume 17, pages 1201–1203 (2020)Cite this article

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CD5+ B lymphocytes, also known as B1 cells, play key roles in the immune system. This subset of B cells is a focus of renewed interest because it is an innate-like B cell population that is responsible for producing natural antibodies, rapid humoral immunity, and immune regulation and has a tendency to undergo leukemic transformation.1,2 It has been unclear, however, whether CD5 is a mere marker of B1 cells or whether it effectively modulates B cell responses and, if so, how. CD5 is a member of the scavenger receptor cysteine-rich (SRCR) superfamily and has a cytoplasmic tail with no enzymatic activity but with a motif that serves as docking sites for phosphorylated Src homology 2 (SH2) domain-containing kinases. In a recent study published in Cellular and Molecular Immunology, we reported that CD5 directly modulates B cell biology.3 These studies revealed that CD5 promotes the activation of Erk1/2 and multiple downstream signaling pathways. Activation of these pathways induces IL-10 production and modulates survival and metabolism. These effects were dependent on extracellular calcium (Ca2+) influx facilitated by upregulation of the transient receptor potential channel 1 (TRPC1) protein. Interestingly, TRPC1 is also typically upregulated in CD5+ B cell chronic lymphocytic leukemia (B-CLL). CD5-induced IL-10 production was independent of B cell receptor (BCR) engagement, as confirmed by targeted CD5 and TRPC1 suppression with siRNAs. Our findings facilitate a better understanding of the mechanisms of CD5+ B cell roles in health and diseases.

CD5 is characteristically expressed in T lymphocytes and is expressed at lower levels in B1 cells, a subset of B cells. B1 cells constitute a large subset in the human fetal spleen and umbilical cord blood but decline to ~10% in adult blood. CD5 is also abundantly expressed in B cells in most patients with B cell malignancies, including B-CLL, mantle cell lymphoma, and marginal zone B cell lymphoma.2 Compelling and, at the time, paradoxical evidence also indicates that CD5+ B cells play important roles in providing rapid first line immunity (innate immunity) and a level of immune regulation.1,2 However, it has been difficult to differentiate between CD5 as a phenotypic marker and as an effective modulator of B cell biology. In a series of experiments, we confirmed that CD5 directly modulates B lymphocyte responses.3 Using cell transfection, we observed that CD5-mediated induction of mitogen-activated protein kinase (MAPK) Erk1/2 activation is key to inducing IL-10 production. This effect was Ca2+-dependent and involved the nonselective Ca2+ channel TRPC1. Using a comprehensive approach to analyze kinase activation with kinome arrays and traditional Western blotting, we discovered that these effects of CD5 were distinct from its suppressive action on BCR-mediated signaling. Studies have also revealed that CD5 induces the activation of a range of important kinases, including Syk, Btk, and PLCγ2, which are upstream effectors of canonical Erk1/2 activation cascades. CD5 also increased the phosphorylation of SHP1, as previously observed in B-CLL cells.4 Immunoprecipitation experiments confirmed that CD5 was associated with SHP1 and c-Cbl but not with the BCR complex (CD79a) when the BCR was not engaged. However, when the BCR was engaged, CD5 coprecipitated with CD79a.

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References

  1. Hayakawa, K. et al. B cells generated by B-1 development can progress to chronic lymphocytic leukemia. Ann. N.Y. Acad. Sci. 1362, 250–255 (2015).

    Article  CAS  PubMed Central  Google Scholar 

  2. Wong, J. B. et al. B-1a cells acquire their unique characteristics by bypassing the pre-BCR selection stage. Nat. Commun. 10, 4768 (2019).

    Article  PubMed Central  Google Scholar 

  3. Garaud, S. et al. CD5 expression promotes IL-10 production through activation of the MAPK/Erk pathway and upregulation of TRPC1 channels in B lymphocytes. Cell Mol. Immunol. 15, 158–170 (2018).

    Article  CAS  Google Scholar 

  4. Tibaldi, E. et al. Lyn-mediated SHP-1 recruitment to CD5 contributes to resistance to apoptosis of B-cell chronic lymphocytic leukemia cells. Leukemia 25, 1768–1781 (2011).

    Article  CAS  Google Scholar 

  5. Muzio, M. et al. Constitutive activation of distinct BCR-signaling pathways in a subset of CLL patients: a molecular signature of anergy. Blood 112, 188–195 (2008).

    Article  CAS  Google Scholar 

  6. Gary-Gouy, H., Harriague, J., Dalloul, A., Donnadieu, E. & Bismuth, G. CD5-negative regulation of B cell receptor signaling pathways originates from tyrosine residue Y429 outside an immunoreceptor tyrosine-based inhibitory motif. J. Immunol. 168, 232–239 (2002).

    Article  CAS  Google Scholar 

  7. Feske, S., Skolnik, E. Y. & Prakriya, M. Ion channels and transporters in lymphocyte function and immunity. Nat. Rev. Immunol. 12, 532–547 (2012).

    Article  CAS  PubMed Central  Google Scholar 

  8. Ma, E. H., Poffenberger, M. C., Wong, A. H. & Jones, R. G. The role of AMPK in T cell metabolism and function. Curr. Opin. Immunol. 46, 45–52 (2017).

    Article  CAS  Google Scholar 

  9. Pekarsky, Y., Drusco, A., Kumchala, P., Croce, C. M. & Zanesi, N. The long journey of TCL1 transgenic mice: lessons learned in the last 15 years. Gene Expr. 16, 129–135 (2015).

    Article  CAS  PubMed Central  Google Scholar 

  10. Alhakeem, S. S. et al. Role of B cell receptor signaling in IL-10 production by normal and malignant B-1 cells. Ann. N.Y. Acad. Sci. 1362, 239–249 (2015).

    Article  CAS  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK

    Taher E. Taher

  2. Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK

    Jonas Bystrom & Rizgar A. Mageed

  3. Canalopathy and Calcium Signaling, INSERM UMR1078, Brest, France

    Olivier Mignen

  4. INSERM ERI29/EA2216, Réseau Epigenetique and Réseau Canaux Ioniques du Cancéropôle Grand Ouest, Brest, France

    Jacques-Olivier Pers & Yves Renaudineau

  5. Laboratory of Immunology and Immunotherapy, CHU Morvan, Brest, France

    Yves Renaudineau

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Correspondence to Rizgar A. Mageed.

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Taher, T.E., Bystrom, J., Mignen, O. et al. CD5 and B lymphocyte responses: multifaceted effects through multitudes of pathways and channels. Cell Mol Immunol 17, 1201–1203 (2020). https://doi.org/10.1038/s41423-020-0490-z

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