Inducible costimulator expression regulates the magnitude of Th2-mediated airway inflammation by regulating the number of Th2 cells.
BACKGROUND
Inducible Costimulator (ICOS) is an important regulator of Th2 lymphocyte function and a potential immunotherapeutic target for allergy and asthma. A SNP in the ICOS 5' promoter in humans is associated with increased atopy and serum IgE in a founder population and increased ICOS surface expression and Th2 cytokine production from peripheral blood mononuclear cells. However, it is unknown if increased ICOS expression contributes to disease progression or is a result of disease pathology.


RESULTS
We developed a mouse model in which ICOS surface expression levels are genetically predetermined to test our hypothesis that genetic regulation of ICOS expression controls the severity of Th2 responses in vivo. Using ICOS+/+ and ICOS+/- mice in a Th2 model of airway inflammation, we found that T cells from the ICOS+/- mice had reduced ICOS expression and decreased Th2-mediated inflammation in vivo. Although the activation status of the T cells did not differ, T cells isolated from the lungs and draining lymph nodes of ICOS+/- mice at the peak of inflammation produced less Th2 cytokines upon stimulation ex vivo. Using 4get mice, which express GFP upon IL-4 transcription, we determined that the decreased Th2 cytokines in ICOS+/- is due to reduced percentage of Th2 cells and not a defect in their ability to produce IL-4.


CONCLUSIONS
These data suggest that in both mice and humans, the level of ICOS surface expression regulates the magnitude of the in vivo Th2 response, perhaps by influencing Th2 differentiation.
Clay
Bryan S
BS
Committee on Immunology, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
Shilling
Rebecca A
RA
Bandukwala
Hozefa S
HS
Moore
Tamson V
TV
Cannon
Judy L
JL
Welcher
Andrew A
AA
Weinstock
Joel V
JV
Sperling
Anne I
AI
D000818:Animals; D000938:Antigen-Presenting Cells; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics* / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D060889:Inducible T-Cell Co-Stimulator Protein; D007249:Inflammation; D015847:Interleukin-4 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008198:Lymph Nodes / Q000378:metabolism; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018418:Th2 Cells / Q000166:cytology*; D014158:Transcription, Genetic
D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; C556692:ICOS protein, human; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D015847:Interleukin-4