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IgT, a primitive immunoglobulin class specialized in mucosal immunity

Nature Immunology volume 11, pages 827–835 (2010)Cite this article

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Abstract

Teleost fish are the most primitive bony vertebrates that contain immunoglobulins. In contrast to mammals and birds, these species are devoid of immunoglobulin A (IgA) or a functional equivalent. This observation suggests that specialization of immunoglobulin isotypes into mucosal and systemic responses took place during tetrapod evolution. Challenging that paradigm, here we show that IgT, an immunoglobulin isotype of unknown function, acts like a mucosal antibody. We detected responses of rainbow trout IgT to an intestinal parasite only in the gut, whereas IgM responses were confined to the serum. IgT coated most intestinal bacteria. As IgT and IgA are phylogenetically distant immunoglobulins, their specialization into mucosal responses probably occurred independently by a process of convergent evolution.

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Figure 1: Purification and structural characterization of IgT.
Figure 2: Identification of a previously unknown B cell lineage that expresses only surface IgT.
Figure 3: Phagocytic and intracellular killing capacities of IgT+ B cells.
Figure 4: Proliferative and immunoglobulin-secreting capacities of IgT+ and IgM+ B cells in response to microbial stimulation.
Figure 5: Accumulation of IgT+ B cells in the GALT of fish that survived infection with C. shasta.
Figure 6: Immune responses in the gut of trout infected with C. shasta are mediated by the IgT system.
Figure 7: Most trout gut luminal bacteria are predominantly coated with IgT.
Figure 8: Gut mucus IgT and IgM associate with a trout pIgR.

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References

  1. Cooper, M.D. & Alder, M.N. The evolution of adaptive immune systems. Cell 124, 815–822 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Alder, M.N. et al. Antibody responses of variable lymphocyte receptors in the lamprey. Nat. Immunol. 9, 319–327 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Flajnik, M.F. & Kasahara, M. Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat. Rev. Genet. 11, 47–59 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Flajnik, M.F. Comparative analyses of immunoglobulin genes: surprises and portents. Nat. Rev. Immunol. 2, 688–698 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Cerutti, A. & Rescigno, M. The biology of intestinal immunoglobulin A responses. Immunity 28, 740–750 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mussmann, R., Du Pasquier, L. & Hsu, E. Is Xenopus IgX an analog of IgA? Eur. J. Immunol. 26, 2823–2830 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Solem, S.T. & Stenvik, J. Antibody repertoire development in teleosts—a review with emphasis on salmonids and Gadus morhua L. Dev. Comp. Immunol. 30, 57–76 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Zapata, A. & Amemiya, C.T. Phylogeny of lower vertebrates and their immunological structures. Curr. Top. Microbiol. Immunol. 248, 67–107 (2000).

    CAS  PubMed  Google Scholar 

  9. Hansen, J.D., Landis, E.D. & Phillips, R.B. Discovery of a unique Ig heavy-chain isotype (IgT) in rainbow trout: Implications for a distinctive B cell developmental pathway in teleost fish. Proc. Natl. Acad. Sci. USA 102, 6919–6924 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Danilova, N., Bussmann, J., Jekosch, K. & Steiner, L.A. The immunoglobulin heavy-chain locus in zebrafish: identification and expression of a previously unknown isotype, immunoglobulin Z. Nat. Immunol. 6, 295–302 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Flajnik, M.F. The last flag unfurled? A new immunoglobulin isotype in fish expressed in early development. Nat. Immunol. 6, 229–230 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Kaattari, S., Evans, D. & Klemer, J. Varied redox forms of teleost IgM: an alternative to isotypic diversity? Immunol. Rev. 166, 133–142 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Li, J. et al. B lymphocytes from early vertebrates have potent phagocytic and microbicidal abilities. Nat. Immunol. 7, 1116–1124 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Rinehart, J.J. & Boulware, T. Microfilament and microtubule function in human monocytes. J. Lab. Clin. Med. 90, 737–743 (1977).

    CAS  PubMed  Google Scholar 

  15. Bartholomew, J.L., Smith, C.S., Rohovec, J.S. & Fryer, J.L. Characterization of the host response to the myxosporean parasite, Ceratomyxa shasta (Noble), by histology, scanning electron microscope, and immunological techniques. J. Fish Dis. 12, 509–522 (1989).

    Article  Google Scholar 

  16. van der Waaij, L.A., Limburg, P.C., Mesander, G. & van der Waaij, D. In vivo IgA coating of anaerobic bacteria in human faeces. Gut 38, 348–354 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Stokes, C.R., Soothill, J.F. & Turner, M.W. Immune exclusion is a function of IgA. Nature 255, 745–746 (1975).

    Article  CAS  PubMed  Google Scholar 

  18. Brandtzaeg, P. Mucosal immunity: induction, dissemination, and effector functions. Scand. J. Immunol. 70, 505–515 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Suzuki, K., Ha, S.A., Tsuji, M. & Fagarasan, S. Intestinal IgA synthesis: a primitive form of adaptive immunity that regulates microbial communities in the gut. Semin. Immunol. 19, 127–135 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Hamuro, K., Suetake, H., Saha, N.R., Kikuchi, K. & Suzuki, Y. A teleost polymeric Ig receptor exhibiting two Ig-like domains transports tetrameric IgM into the skin. J. Immunol. 178, 5682–5689 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Feng, L.N. et al. Molecular cloning and functional analysis of polymeric immunoglobulin receptor gene in orange-spotted grouper (Epinephelus coioides). Comp. Biochem. Physiol. 154, 282–289 (2009).

    Article  Google Scholar 

  22. Woof, J.M. & Kerr, M.A. The function of immunoglobulin A in immunity. J. Pathol. 208, 270–282 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Snoeck, V., Peters, I.R. & Cox, E. The IgA system: a comparison of structure and function in different species. Vet. Res. 37, 455–467 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Jansson, E. et al. Monoclonal antibodies to lymphocytes of rainbow trout (Oncorhynchus mykiss). Fish Shellfish Immunol. 14, 239–257 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Miyadai, T., Ootani, M., Tahara, D., Aoki, M. & Saitoh, K. Monoclonal antibodies recognising serum immunoglobulins and surface immunoglobulin-positive cells of puffer fish, torafugu (Takifugu rubripes). Fish Shellfish Immunol. 17, 211–222 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Kollner, B., Wasserrab, B., Kotterba, G. & Fischer, U. Evaluation of immune functions of rainbow trout (Oncorhynchus mykiss)—how can environmental influences be detected? Toxicol. Lett. 131, 83–95 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Chen, K. et al. Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell-stimulating programs in basophils. Nat. Immunol. 10, 889–898 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rombout, J.H., Taverne-Thiele, A.J. & Villena, M.I. The gut-associated lymphoid tissue (GALT) of carp (Cyprinus carpio L.): an immunocytochemical analysis. Dev. Comp. Immunol. 17, 55–66 (1993).

    Article  CAS  PubMed  Google Scholar 

  29. Bernard, D. et al. Phenotypic and functional similarity of gut intraepithelial and systemic T cells in a teleost fish. J. Immunol. 176, 3942–3949 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Bromage, E.S., Kaattari, I.M., Zwollo, P. & Kaattari, S.L. Plasmablast and plasma cell production and distribution in trout immune tissues. J. Immunol. 173, 7317–7323 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Zapata, A., Diez, B., Cejalvo, T., Gutierrez-de Frias, C. & Cortes, A. Ontogeny of the immune system of fish. Fish Shellfish Immunol. 20, 126–136 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Sommerset, I., Krossoy, B., Biering, E. & Frost, P. Vaccines for fish in aquaculture. Expert Rev. Vaccines 4, 89–101 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Hart, S., Wrathmell, A.B., Harris, J.E. & Grayson, T.H. Gut immunology in fish: a review. Dev. Comp. Immunol. 12, 453–480 (1988).

    Article  CAS  PubMed  Google Scholar 

  34. Nash, P.V. & Speer, C.A. B-lymphocyte responses in the large intestine and mesenteric lymph nodes of mice infected with Eimeria falciformis (Apicomplexa). J. Parasitol. 74, 144–152 (1988).

    Article  CAS  PubMed  Google Scholar 

  35. Rose, M.E., Peppard, J.V. & Hobbs, S.M. Coccidiosis: characterization of antibody responses to infection with Eimeria nieschulzi. Parasite Immunol. 6, 1–12 (1984).

    Article  CAS  PubMed  Google Scholar 

  36. Kim, D.H., Brunt, J. & Austin, B. Microbial diversity of intestinal contents and mucus in rainbow trout (Oncorhynchus mykiss). J. Appl. Microbiol. 102, 1654–1664 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Garrett, W.S., Gordon, J.I. & Glimcher, L.H. Homeostasis and inflammation in the intestine. Cell 140, 859–870 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mason, K.L., Huffnagle, G.B., Noverr, M.C. & Kao, J.Y. Overview of gut immunology. Adv. Exp. Med. Biol. 635, 1–14 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Zhang, Y.A. et al. Conservation of structural and functional features in a primordial CD80/86 molecule from rainbow trout (Oncorhynchus mykiss), a primitive teleost fish. J. Immunol. 183, 83–96 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Stocking, R.W., Holt, R.A., Foot, J.S. & Bartholomew, J.L. Spatial and temporal occurrence of the salmonid parasite Ceratomyxa shasta in the Oregon-California Klamath river basin. J. Aquat. Anim. Health 18, 194–202 (2006).

    Article  Google Scholar 

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Acknowledgements

We thank G. Warr (National Science Foundation) for anti–trout IgM; D. Artis and P. Boudinot for critical reading of the manuscript; the Morphology Core of the Center for Molecular Studies in Digestive and Liver Diseases of the University of Pennsylvania, especially G. Swain, for help and advice on immunohistochemistry; C. Pletcher and the staff of the Flow Cytometry and Cell Sorting Facility of the University of Pennsylvania for cell sorting; and Y. Liu, L. Zhang and C. Zhou for technical assistance in cell transfection and immunofluorescence microscopy analyses. Supported by the National Science Foundation (NSF-MCB-0719599 to J.O.S.), the US National Institutes of Health (R01GM085207-01 to J.O.S.) and the United States Department of Agriculture (USDA-NRI 2006-01619 and USDA-NRI 2007-01719 to J.O.S.).

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  1. Yong-An Zhang and Irene Salinas: These authors equally contributed to this work.

Authors and Affiliations

  1. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Yong-An Zhang, Irene Salinas, Jun Li, David Parra, Zhen Xu & J Oriol Sunyer

  2. Department of Microbiology, Center for Fish Disease Research, Oregon State University, Corvallis, Oregon, USA

    Sarah Bjork & Jerri Bartholomew

  3. Research Division, Clear Springs Foods, Buhl, Idaho, USA

    Scott E LaPatra

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Contributions

Y.-A.Z. purified trout IgT, developed polyclonal and monoclonal antibodies to IgT and a polyclonal antibody to trout pIgR, analyzed the biochemical features of IgT and the gene-expression profiles of IgT+ and IgM+ cells, measured specific IgT and IgM titers to C. shasta and did all experiments involved in cloning and functional studies of trout pIgR; I.S. developed the protocols to obtain leukocytes and bacteria from trout GALT and the immunohistochemistry protocols to detect IgT+ and IgM+ cells and C. shasta in trout lymphoid tissues and did immunohistochemistry studies and flow cytometry of IgT+ and IgM+ cells in trout GALT and gut luminal bacteria; J.L. did the flow cytometry of IgT+ and IgM+ cells of trout lymphoid organs, measured the phagocytotic capacity and intracellular bacterial killing of B cells and contributed to the evaluation of total IgT and IgM concentrations in serum and gut mucus, together with Y.-A.Z.; D.P. analyzed IgT and IgM coating on gut bacteria, did the B cell proliferation studies and tested the production of IgT and IgM after stimulation with microbial products; S.B. infected fish with C. shasta and provided samples from survivor and control fish; Z.X. contributed to the evaluation of the production of IgT and IgM by cultured trout leukocytes and sorted B cells; S.E.L. and J.B. contributed to the experimental design and discussions related to C. shasta infection; J.O.S. designed the overall study, contributed to data analysis and wrote the main body of the paper; and all authors read and commented on the paper. J.L. and D.P. contributed equally to this work.

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Correspondence to J Oriol Sunyer.

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Zhang, YA., Salinas, I., Li, J. et al. IgT, a primitive immunoglobulin class specialized in mucosal immunity. Nat Immunol 11, 827–835 (2010). https://doi.org/10.1038/ni.1913

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