Abstract
IL-23 but not IL-12 is essential for the development of autoimmune tissue inflammation in mice. Conversely, IL-12 and IL-23 impact on the polarization of Th1 and Th17 cells, respectively. While both polarized T helper populations can mediate autoimmune inflammation, their redundancy in the pathogenesis of EAE indicates that IL-23 exerts its crucial influence on the disease independent of its T helper polarizing capacity. To study the impact of IL-23 and IL-12 on the behavior of encephalitogenic T cells in vivo, we generated BM-chimeric mice in which we can trace individual populations of IL-23 or IL-12 responsive T helper cells during EAE. We observed that T cells, which lack IL-12Rbeta1 (no IL-12 and IL-23 signaling), fail to invade the CNS and do not acquire a Th17 phenotype. In contrast, loss of IL-12 signaling prevents Th1 polarization but does not prevent T-cell entry into the CNS. The loss of IL-12R engagement does not appear to alter T-cell expansion but leads to their accumulation in secondary lymphoid organs. We found that IL-23 licenses T cells to invade the target tissue and to exert their effector function, whereas IL-12 is critical for Th1 differentiation, but does not influence the pathogenic capacity of auto-reactive T helper cells in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow / metabolism
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Bone Marrow / pathology
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Bone Marrow / radiation effects
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / pathology
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Central Nervous System / immunology
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Central Nervous System / metabolism*
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Central Nervous System / pathology
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / metabolism
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Flow Cytometry
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Forkhead Transcription Factors / metabolism
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Interferon-beta / metabolism
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Interleukin-17 / metabolism*
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Interleukin-23 / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mutation
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Receptors, Interleukin / genetics
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Receptors, Interleukin / metabolism
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Receptors, Interleukin-12 / genetics
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Receptors, Interleukin-12 / metabolism
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Signal Transduction / immunology
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T-Lymphocytes, Helper-Inducer / immunology
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T-Lymphocytes, Helper-Inducer / metabolism*
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T-Lymphocytes, Helper-Inducer / pathology
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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T-Lymphocytes, Regulatory / pathology
Substances
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Homeodomain Proteins
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Interleukin-17
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Interleukin-23
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Receptors, Interleukin
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Receptors, Interleukin-12
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interleukin-23 receptor, mouse
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RAG-1 protein
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Interferon-beta