ICOS deficiency results in exacerbated IL-17 mediated experimental autoimmune encephalomyelitis.
BACKGROUND
Inducible costimulatory molecule (ICOS) is important for the effector function of T cells, especially for Th2 and T cell dependent B cell responses. However, it has been shown that ICOS is required for the differentiation of Th17 cells. Since IL-17 has been identified as a major cytokine involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the enhanced severity of EAE in ICOS-deficient mice (ICOS(-/-)) mice is unexpected.


METHODS
To better understand the role of ICOS and of IL-17 in EAE, we induced EAE in ICOS(-/-) by immunization with myelin oligodendrocyte glycoprotein peptide (MOG(35-55)) in complete Freund's adjuvant.


RESULTS
As previously reported, we found that ICOS(-/-) mice developed more severe EAE. Upon restimulation with MOG(35-55,) splenocytes from ICOS(-/-) mice with EAE produced higher amounts of IL-17 and ICOS(-/-) mice had a higher expression of IL-17, IL-6, and TGF-beta mRNA in the spinal cords at the onset of the disease. Finally, the blockade of IL-17 strongly inhibited disease even in ICOS(-/-) mice, showing that IL-17 is playing a major role in the pathogenesis of EAE both in WT and ICOS(-/-) mice.


CONCLUSIONS
In conclusion, MOG immunization induces MOG-specific Th17 cells also in ICOS(-/-) mice, and a higher expression of IL-17 and of Th17-driving cytokines IL-6 and TGF-beta in the central nervous system at the onset of EAE that correlates with their more severe disease.
Galicia
Georgina
G
Division of Clinical Immunology, Faculty of Medicine, Catholic University of Leuven, 3000 Leuven, Belgium. georgina.galiciarosas@student.kuleuven.be
Kasran
Ahmad
A
Uyttenhove
Catherine
C
De Swert
Kathleen
K
Van Snick
Jacques
J
Ceuppens
Jan L
JL
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006023:Glycoproteins / Q000276:immunology; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000276:immunology
D000945:Antigens, Differentiation, T-Lymphocyte; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006023:Glycoproteins; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D020381:Interleukin-17; D015850:Interleukin-6; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; C445081:myelin oligodendrocyte glycoprotein (35-55); D007371:Interferon-gamma