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.

Chen Y, Rosloniec E, Goral MI, Boothby M, Chen J
J Immunol. 2001 166 (6): 4163-9

PMID: 11238667 · DOI:10.4049/jimmunol.166.6.4163

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.

MeSH Terms (25)

Amino Acid Sequence Animals Arthritis, Experimental Autoantibodies Cattle Cell Movement Collagen Cytokines Eosinophils Epitopes, T-Lymphocyte Hindlimb Immunoglobulin G Lymphocyte Activation Mice Mice, Inbred C57BL Mice, Inbred DBA Mice, Transgenic Molecular Sequence Data Receptors, Cytokine Receptors, Interleukin-2 Receptors, Interleukin-4 Recombinant Fusion Proteins Th2 Cells Transgenes Up-Regulation

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