Induction of Diabetes in Nonobese Diabetic Mice by Th2 T Cell Clones from a TCR Transgenic Mouse

Poulin, Michelle; Haskins, Kathryn

doi:10.4049/jimmunol.164.6.3072

Cited by 38 publications

(44 citation statements)

References 50 publications

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“…Such conditioning would be very limited in autoimmune responses. This hypothesis is supported by the adoptive transfer of transgenic CD4 T cells in nonobese diabetic (NOD).scid mice (15) and the induction of diabetes in rat insulin promoter (RIP)-OVAtransgenic mice coinjected with CD4 and CD8 OVA-specific T cells (16,17).…”

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confidence: 71%

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CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity

Calzascia

Pellegrini

Lin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

114

104

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There are many inhibitory mechanisms that function at the cellular and molecular levels to maintain tolerance. Despite this, self-reactive clones escape regulatory mechanisms and cause autoimmunity in certain circumstances. We hypothesized that the same mechanisms that permit T cells to expand during homeostatic proliferation may inadvertently promote autoimmunity under certain conditions. One major homeostatic cytokine is IL-7, and studies have linked it or its receptor to the development of multiple sclerosis and other autoimmune diseases. We show in a model of ␤-islet cell self-reactivity that the transfer of activated autoreactive CD4 T cells can prime and expand endogenous autoreactive CD8 T cells in a CD28-and CD40-dependent manner through the licensing of dendritic cells. Despite this, mice do not develop diabetes. However, the provision of exogenous IL-7 or the physiological production of IL-7 associated with lymphopenia was able to profoundly promote the expansion of self-reactive clones even in the presence of regulatory T cells. Autoimmune diabetes rapidly ensued with CD4 help and the subsequent activation of CD8 T cells, which contributed to disease progression. With the advent of many biologicals targeting TNF␣, IL-6, and IL-1 and their effective use in the treatment of autoimmune diseases, we propose that IL-7 and its receptor may be promising targets for biological agents in the treatment of autoimmunity.lymphocyte homeostasis ͉ CD8 T cells ͉ cytokines ͉ dendritic cells ͉ cyclophosphamide

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confidence: 71%

“…If self-reactive CD4 T cells do become activated and expand in the presence of a permissive cytokine environment, how do they then participate in the pathogenesis of autoimmune disease (15)(16)(17)? The exact mechanism as to how CD4 T cells promote and sustain an autoimmune response is still unclear.…”

mentioning

confidence: 99%

CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity

Calzascia

Pellegrini

Lin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

114

104

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“…Regulation of IDDM by treatment of animals with Ags may be epitope dependent and correlate with an induction of Th2 cells (15,16). However, Th2 cells can also cause the development of the disease (17,18). Furthermore, a shift to Th2 cells after peptide treatment of patients may induce deleterious allergic or autoimmune response (19).…”

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confidence: 99%

Induction of Autoantigen-Specific Th2 and Tr1 Regulatory T Cells and Modulation of Autoimmune Diabetes

Chen

Lee

Yun

et al. 2003

The Journal of Immunology

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Autoantigen-based immunotherapy can modulate autoimmune diabetes, perhaps due to the activation of Ag-specific regulatory T cells. Studies of these regulatory T cells should help us understand their roles in diabetes and aid in designing a more effective immunotherapy. We have used class II MHC tetramers to isolate Ag-specific T cells from nonobese diabetic (NOD) mice and BALB/c mice treated with glutamic acid decarboxylase 65 peptides (p206 and p221). Based on their cytokine secretion profiles, immunization of NOD mice with the same peptide induced different T cell subsets than in BALB/c mice. Treatment of NOD mice induced not only Th2 cells but also IFN-γ/IL-10-secreting T regulatory type 1 (Tr1) cells. Adoptive transfer experiments showed that isolated tetramer+ T cells specific for p206 or p221 could inhibit diabetes development. These cells were able to suppress the in vitro proliferation of other NOD mouse T cells without cell-cell contact. They performed their regulatory functions probably by secreting cytokines, and Abs against these cytokines could block their suppressive effect. Interestingly, the presence of both anti-IL-10 and anti-IFN-γ could enhance the target cell proliferation, suggesting that Tr1 cells play an important role. Further in vivo experiments showed that the tetramer+ T cells could block diabetogenic T cell migration into lymph nodes. Therefore, treatment of NOD mice with autoantigen could induce Th2 and Tr1 regulatory cells that can suppress the function and/or block the migration of other T cells, including diabetogenic T cells, and inhibit diabetes development.

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“…Specifically, infiltration of eosinophils in the islets and infiltration of mast cells in the spinal cord were observed for insulin-dependent diabetes mellitus and EAE, respectively (29,30). Moreover, adoptive transfer of long term T cell clones with a fixed Th2 cytokine profile caused diabetes in immunocompetent mice (31). Our results demonstrate that even in the absence of adoptive transfer and without an expanded population of Ag-specific T cells, sustained elevation of type 2 responses may not be benign and has the potential to cause clinical disease in animal models.…”

Section: Discussionmentioning

confidence: 99%

Redirection of T Cell Effector Function In Vivo and Enhanced Collagen-Induced Arthritis Mediated by an IL-2Rβ/IL-4Rα Chimeric Cytokine Receptor Transgene

Chen

Rosloniec

Goral³

et al. 2001

The Journal of Immunology

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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-2Rβ/IL-4Rα 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-2Rβ/IL-4Rα 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-γ 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.

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Induction of Diabetes in Nonobese Diabetic Mice by Th2 T Cell Clones from a TCR Transgenic Mouse

Cited by 38 publications

References 50 publications

CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity

CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity

Induction of Autoantigen-Specific Th2 and Tr1 Regulatory T Cells and Modulation of Autoimmune Diabetes

Redirection of T Cell Effector Function In Vivo and Enhanced Collagen-Induced Arthritis Mediated by an IL-2Rβ/IL-4Rα Chimeric Cytokine Receptor Transgene

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