IL-17 cytokines are best known for their roles in immune defense against bacterial and fungal infections and in the pathogenesis of inflammatory autoimmune diseases including rheumatoid arthritis(RA), multiple sclerosis(MS), and psoriasis. Cells that are known to be producers of IL-17 include CD4+ TH17 T cells, CD8+ TC17 T cells, type 3 innate lymphoid cells (ILC3/lymphoid tissue-inducer cells), gd T cells, and NKT cells. However, in a recent article in Nature Immunology, Bermejo et. al demonstrate that B cells are primary producers of IL-17 during infection with the protozoan parasite,Trypanosoma cruzi. Furthermore, B cells activated IL-17 production through an entirely novel pathway.
IL-17 comprises a family of six related homo- or hetero-dimeric functioning cytokines (IL-17A – IL-17F) that signal through a complex family of multimeric IL-17 receptors (IL-17RA – IL-17RE). IL-17 cytokines activate a unique signaling pathway through the adaptor protein Act1 which leads to induction of several transcription factors including NF-kB, IκBζ, C/EBPδ, C/EBPβ, MAPK, and PI3K.
In the study by Bermejo et. al, the authors sought to identify all of the cell types producing IL-17 during in vivo infection of mice with T. Cruzi. Interestingly, the majority of splenic cells producing IL-17 at 10 and 19 days post-infection were CD3– and instead expressed CD19 and B220, markers of B cells. Further characterization of these cells revealed expression of the plasmablast marker CD138, but not germinal center B cell markers. IL-17+B220+ cells were absent in T. Cruzi infected B cell-deficient μMT mice and these mice were less able to control the infection and had higher levels of IFN-gamma and TNF. Thus, B cells were not only the major IL-17 producers during T. Cruzi infection, but played a major role in protective immune responses and limiting immune pathology.
In mice, the generation of IL-17 producing TH17 cells is driven by IL-6, IL-23, and the transcription factors RORgammaT, ROR-alpha, and Ahr. However, IL-17 producing B cells were still generated in T. Cruzi infected mice or B cells lacking IL-6, IL-23R, RORgammaT, Ahr, or treated with inhibitors of ROR-alpha. In vitro exposure of purified B cells to T. Cruzi induced production of IL-17; however this was not mimicked by incubation of B cells with TLR2, TLR4, or TLR9 ligands, further indicating the lack of a role for inflammatory cytokines upregulated by TLRs in inducing IL-17 in B cells. T cells did not produce IL-17 in response to T. Cruzi. Thus the known regulators of IL-17 producing cells were not involved in the unique induction of IL-17 in B cells by T. Cruzi.
The authors focused on T. Cruzi trans-sialidase, a surface GPI-anchored enzyme, as being the potential IL-17 inducing signal, due to its previously described activity as a B cell mitogen. Treatment of B cells with recombinant enzymatically active trans-sialidase recapitulated IL-17 production and a blocking antibody against the enzymatic site of trans-sialidase completely inhibited the induction of IL-17 during T. Cruzi exposure. Through a series of experiments, the authors determined that trans-sialidase-mediated sialylation of the surface marker CD45 was required for B cell IL-17 production. The signaling pathway downstream of CD45 leading to IL-17 induction was found to involve Src kinases, Btk, and Tec.
Finally, the authors examined if this phenomenon occurs in human B cells as well. CD19+ B cells were isolated from tonsils and the production of IL-17 was also seen in response to T. Cruzi exposure in a CD45 and Btk dependant fashion.
In conclusion, this was an exciting study that demonstrated not only that B cells are major IL-17 producers during parasitic infections, but also identified a unique signaling pathway that mediates this effect in both mice and humans. Many questions remain about how this unique signal transduction pathway operates only in plasmablast B cells but not other cell types, despite the widespread expression of CD45 by hematopoietic cells. Furthermore, the role of IL-17 production by B cells in immune responses to other pathogens that express trans-sialidases as well as the role for these B cells in IL-17-driven immune pathologies remains to be explored.
Trypanosoma cruzi trans-sialidase initiates a program independent of the transcription factors RORγt and Ahr that leads to IL-17 production by activated B cells. Bermejo DA, Jackson SW, Gorosito-Serran M, Acosta-Rodriguez EV, Amezcua-Vesely MC, Sather BD, Singh AK, Khim S, Mucci J, Liggitt D, Campetella O, Oukka M, Gruppi A, Rawlings DJ. Nat Immunol. 2013 May;14(5):514-22. doi: 10.1038/ni.2569.
IL-17-producing B cells combat parasites. León B, Lund FE. Nat Immunol. 2013 May;14(5):419-21. doi: 10.1038/ni.2593.
Recent advances in the IL-17 cytokine family. Gaffen SL. Curr Opin Immunol. 2011 Oct;23(5):613-9. doi: 10.1016/j.coi.2011.07.006.
Development and evolution of RORγt+ cells in a microbe’s world. Eberl G. Immunol Rev. 2012 Jan;245(1):177-88. doi: 10.1111/j.1600-065X.2011.01071.x.