Adaptive autoimmunity and Foxp3-based immunoregulation in zebrafish.
BACKGROUND
Jawed vertebrates generate their immune-receptor repertoire by a recombinatorial mechanism that has the potential to produce harmful autoreactive lymphocytes. In mammals, peripheral tolerance to self-antigens is enforced by Foxp3(+) regulatory T cells. Recombinatorial mechanisms also operate in teleosts, but active immunoregulation is thought to be a late incorporation to the vertebrate lineage.


RESULTS
Here we report the characterization of adaptive autoimmunity and Foxp3-based immunoregulation in the zebrafish. We found that zebrafish immunization with an homogenate of zebrafish central nervous system (zCNS) triggered CNS inflammation and specific antibodies. We cloned the zebrafish ortholog for mammalian Foxp3 (zFoxp3) which induced a regulatory phenotype on mouse T cells and controlled IL-17 production in zebrafish embryos.


CONCLUSIONS
Our findings demonstrate the acquisition of active mechanisms of self-tolerance early in vertebrate evolution, suggesting that active regulatory mechanisms accompany the development of the molecular potential for adaptive autoimmunity. Moreover, they identify the zebrafish as a tool to study the molecular pathways controlling adaptive immunity.
Quintana
Francisco J
FJ
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. fquintana@rics.bwh.harvard.edu
Iglesias
Antonio H
AH
Farez
Mauricio F
MF
Caccamo
Mario
M
Burns
Evan J
EJ
Kassam
Nasim
N
Oukka
Mohamed
M
Weiner
Howard L
HL
D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity; D019070:Cell Lineage; D017124:Conserved Sequence; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006801:Humans; D007107:Immune System; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D017434:Protein Structure, Tertiary; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000276:immunology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000502:physiology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D018336:Receptors, Aryl Hydrocarbon; D029961:Zebrafish Proteins; C554833:foxp3a protein, zebrafish