Redirection of T cell effector function in vivo and enhanced collagen-induced arthritis mediated by an IL-2R beta/IL-4R alpha chimeric cytokine receptor transgene.
Chronic inflammatory autoimmune diseases such as diabetes, experimental autoimmune encephalomyelitis, and collagen-induced arthritis (CIA) are associated with type 1 (Th1, Tc1) T cell-dependent responses against autoantigens. Immune deviation toward type 2 (Th2, Tc2) response has been proposed as a potential means of gene therapy or immunomodulation to treat autoimmune diseases based on evidence that type 2 cytokines can prevent or alleviate these conditions. In this report we assessed the effects of elevated type 2 responses on CIA using transgenic mice expressing an IL-2R beta/IL-4R alpha chimeric cytokine receptor transgene specifically in T cells. In response to IL-2 binding, this chimeric receptor transduces IL-4-specific signals and dramatically enhances type 2 responses. In contrast to published reports of Th2-mediated protection, CIA was exacerbated in IL-2R beta/IL-4R alpha chimeric receptor transgenic mice, with increased disease incidence, severity, and earlier disease onset. The aggravated disease in transgenic mice was associated with an increase in type 2 cytokines (IL-4, IL-5, IL-10) and an increase in collagen-specific IgG1 levels. However, IFN-gamma production is not affected significantly in the induction phase of the disease. There is also an extensive eosinophilic infiltration in the arthritic joints of the transgenic animal, suggesting a direct contribution of type 2 response to joint inflammation. Taken together, our findings provide novel evidence that enhancement of a polyclonal type 2 response in immunocompetent hosts may exacerbate an autoimmune disease such as CIA, rather than serving a protective role. This finding raises significant caution with regard to the potential use of therapeutic approaches based on immune deviation toward type 2 responses.
Division of Rheumatology, Department of Medicine, Vanderbilt University Medical School, Nashville, TN 37232, USA.
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Y
Chen
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Rosloniec
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MI
Goral
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Boothby
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J
Chen
D000595:Amino Acid Sequence; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood; D002417:Cattle; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003094:Collagen / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004804:Eosinophils / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006614:Hindlimb; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018121:Receptors, Cytokine / Q000235:genetics* / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000235:genetics* / Q000502:physiology; D019948:Receptors, Interleukin-4 / Q000235:genetics* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology*; D019076:Transgenes / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D001323:Autoantibodies; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D018121:Receptors, Cytokine; D015375:Receptors, Interleukin-2; D019948:Receptors, Interleukin-4; D011993:Recombinant Fusion Proteins; D003094:Collagen