CD4-Transgenic Zebrafish Reveal Tissue-Resident Th2- and Regulatory T Cell-like Populations and Diverse Mononuclear Phagocytes.
CD4+T cells are at the nexus of the innate and adaptive arms of the immune system. However, little is known about the evolutionary history of CD4+T cells, and it is unclear whether their differentiation into specialized subsets is conserved in early vertebrates. In this study, we have created transgenic zebrafish with vibrantly labeled CD4+cells allowing us to scrutinize the development and specialization of teleost CD4+leukocytes in vivo. We provide further evidence that CD4+macrophages have an ancient origin and had already emerged in bony fish. We demonstrate the utility of this zebrafish resource for interrogating the complex behavior of immune cells at cellular resolution by the imaging of intimate contacts between teleost CD4+T cells and mononuclear phagocytes. Most importantly, we reveal the conserved subspecialization of teleost CD4+T cells in vivo. We demonstrate that the ancient and specialized tissues of the gills contain a resident population of il-4/13b-expressing Th2-like cells, which do not coexpress il-4/13a Additionally, we identify a contrasting population of regulatory T cell-like cells resident in the zebrafish gut mucosa, in marked similarity to that found in the intestine of mammals. Finally, we show that, as in mammals, zebrafish CD4+T cells will infiltrate melanoma tumors and obtain a phenotype consistent with a type 2 immune microenvironment. We anticipate that this unique resource will prove invaluable for future investigation of T cell function in biomedical research, the development of vaccination and health management in aquaculture, and for further research into the evolution of adaptive immunity.
Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, United Kingdom.
Christopher T
0000-0002-0460-4309
CT
Dee
Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, United Kingdom.
Raghavendar T
0000-0002-6891-5181
RT
Nagaraju
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, United Kingdom.|Department of Haematology, University of Cambridge, Cambridge CB2 0PT, United Kingdom.|Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge CB2 1QR, United Kingdom.
Emmanouil I
0000-0002-2771-5562
EI
Athanasiadis
Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield S10 2RX, United Kingdom.|Bateson Centre, University of Sheffield, Sheffield S10 2TN, United Kingdom; and.
Caroline
C
Gray
Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, United Kingdom.
Laura
L
Fernandez Del Ama
Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield S10 2RX, United Kingdom.|Bateson Centre, University of Sheffield, Sheffield S10 2TN, United Kingdom; and.
Simon A
SA
Johnston
Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, Aberdeen AB24 3UU, United Kingdom.
Christopher J
0000-0001-8781-176X
CJ
Secombes
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, United Kingdom; adam.hurlstone@manchester.ac.uk as889@cam.ac.uk.|Department of Haematology, University of Cambridge, Cambridge CB2 0PT, United Kingdom.|Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge CB2 1QR, United Kingdom.
Ana
0000-0003-3204-9311
A
Cvejic
Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, United Kingdom; adam.hurlstone@manchester.ac.uk as889@cam.ac.uk.
Adam F L
0000-0001-5260-9457
AF
Hurlstone
D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation; D002478:Cells, Cultured; D005393:Fish Diseases / Q000276:immunology*; D005880:Gills / Q000276:immunology; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008322:Mammals; D008545:Melanoma / Q000276:immunology*; D012157:Mononuclear Phagocyte System; D009374:Neoplasms, Experimental; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D015027:Zebrafish / Q000276:immunology*
D018793:Interleukin-13; D015847:Interleukin-4
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