IL-2 and autoimmune disease

Schimpl, Anneliese; Berberich, Ingolf; Kneitz, Burkhardt; Krämer, Susanne; Santner-Nanan, Brigitte; Wagner, Sabine; Wolf, Mary C.; Hünig, Thomas

doi:10.1016/s1359-6101(02)00022-9

Cited by 86 publications

(67 citation statements)

References 53 publications

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“…Similarly to the phenotype of Stim1 Ϫ/Ϫ mice described here, it came as a surprise that IL-2-deficient mice (35) were not overtly immunodeficient, but developed a lymphoproliferative disease sharing many characteristics with that of Stim1 Ϫ/Ϫ mutants (36). Although in IL-2-deficient mice lymphoproliferation evolves mainly due to the inability to maintain a functional Treg cell compartment exerting immunoregulation in trans, which is further aggravated by a reduced susceptibility of IL-2-deficient T cells to CD95-mediated cell death in cis (36) Because autoreactive T cells need costimulation through CD28 to produce IL-2 (37,38), the degree of costimulation received under noninflammatory conditions is comparatively weak and autoreactive T cells might even recognize peptide-MHC complexes containing their "cognate" autoantigenic peptide without a costimulatory signal. Isolated stimulation of the TCR on purified T cells in vitro or culture of purified T cells in the presence of ionomycin, however, have been known for a long time to induce a state of anergy (39).…”

Section: Discussionmentioning

confidence: 54%

STIM1-Independent T Cell Development and Effector Function In Vivo

Beyersdorf

Braun²,

Vögtle³

et al. 2009

The Journal of Immunology

120

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Store-operated Ca2؉ entry (SOCE) is believed to be of pivotal importance in T cell physiology. To test this hypothesis, we generated mice constitutively lacking the SOCE-regulating Ca 2؉ sensor stromal interaction molecule 1 (STIM1). In vitro analyses showed that SOCE and Ag receptor complex-triggered Ca 2؉ flux into STIM1-deficient T cells is virtually abolished. In vivo, STIM1-deficient mice developed a lymphoproliferative disease despite normal thymic T cell maturation and normal frequencies of CD4 ؉ Foxp3؉ regulatory T cells. Unexpectedly, STIM1-deficient bone marrow chimeric mice mounted humoral immune responses after vaccination and STIM1-deficient T cells were capable of inducing acute graft-versus-host disease following adoptive transfer into allogeneic hosts. These results demonstrate that STIM1-dependent SOCE is crucial for homeostatic T cell proliferation, but of much lesser importance for thymic T cell differentiation or T cell effector functions.

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Section: Discussionmentioning

confidence: 54%

STIM1-Independent T Cell Development and Effector Function In Vivo

Beyersdorf

Braun²,

Vögtle³

et al. 2009

The Journal of Immunology

120

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“…A similar disease is observed in mice deficient in IL-2R␣ (CD25) (16) and IL-2R␤ (17). The cause of the disease in IL-2 signaling-deficient mice is now thought to be multifactorial, and two causes are commonly cited (18). First, T cells deficient in IL-2 signaling have decreased susceptibility to Fas-mediated cell death (19).…”

mentioning

confidence: 83%

Transgenic Expression of CTLA-4 Controls Lymphoproliferation in IL-2-Deficient Mice

Hwang

Sweatt

Mashayekhi

et al. 2004

The Journal of Immunology

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IL-2-deficient mice develop a lymphoproliferative and autoimmune disease characterized by autoimmune hemolytic anemia (AHA) and inflammatory bowel disease. We have previously reported that IL-2 is necessary for optimal up-regulation of CTLA-4, an inducible negative regulator of T cell activation. In this study, we have tested the hypothesis that reduced expression of CTLA-4 in IL-2-deficient T cells contributes to the pathogenesis of disease in IL-2-deficient mice. Expression of CTLA-4 as a transgene completely prevented lymphoaccumulation and AHA in IL-2-deficient mice. The normalization of T cell numbers was due to inhibition of expansion of conventional CD4+CD25− T cells rather than to rescue of the numbers or function of CD4+CD25+ regulatory T cells, suggesting that CTLA-4 expression on conventional T cells plays a role in maintaining normal T cell homeostasis. In addition, the inhibitory effect of the CTLA-4 transgene on T cell expansion was at least in part independent of CD28 expression. Our results suggest that deficient CTLA-4 expression on conventional T cells contributes to the pathophysiology of the lymphoproliferative disease and AHA in IL-2-deficient mice. Thus, restoring CTLA-4 expression in T cells may be an attractive strategy to control clinical autoimmune diseases in which CTLA-4 expression is reduced.

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“…However, all of these experiments should be interpreted with some caution, since i) the immune systems of these mice are dysregulated, and ii) competition between T cells for antigen and growth factors is an important component that is not present in mice completely lacking IL-2 or its receptors. The later phases of the immune response have been particularly difficult to study due to the various forms of autoimmune disease that occur in these mouse strains [19]. Several recent studies investigating the role of IL-2 in healthy hosts do not support an essential role of IL-2 in promoting the priming and differentiation of effector T cells [20][21][22] but indicate a role for IL-2R signaling in secondary expansion of memory CD8 + T cells [23].…”

Section: Introductionmentioning

confidence: 99%

Differential role of IL‐2R signaling for CD8⁺ T cell responses in acute and chronic viral infections

Bachmann¹,

et al. 2007

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IL‐2 is a cytokine with multiple and even divergent functions; it has been described as a key cytokine for in vitro T cell proliferation but is also essential for down‐regulating T cell responses by inducing activation‐induced cell death as well as regulatory T cells. The in vivo analysis of IL‐2 function in regulating specific T cell responses has been hampered by the fact that mice deficient in IL‐2 or its receptors develop lymphoproliferative diseases and/or autoimmunity. Here we generated chimeric mice harboring both IL‐2R‐competent and IL‐2R‐deficient T cells and assessed CD8+ T cell induction, function and maintenance after acute or persistent viral infections. Induction and maintenance of CD8+ T cells were relatively independent of IL‐2R signaling during acute/resolved viral infection. In marked contrast, IL‐2 was crucial for secondary expansion of memory CD8+ T cells and for the maintenance of virus‐specific CD8+ T cells during persistent viral infections. Thus, depending on the chronicity of antigen exposure, IL‐2R signaling is either essential or largely dispensable for induction and maintenance of virus‐specific CD8+ T cell responses.

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IL-2 and autoimmune disease

Cited by 86 publications

References 53 publications

STIM1-Independent T Cell Development and Effector Function In Vivo

STIM1-Independent T Cell Development and Effector Function In Vivo

Transgenic Expression of CTLA-4 Controls Lymphoproliferation in IL-2-Deficient Mice

Differential role of IL‐2R signaling for CD8⁺ T cell responses in acute and chronic viral infections

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IL-2 and autoimmune disease

Cited by 86 publications

References 53 publications

STIM1-Independent T Cell Development and Effector Function In Vivo

STIM1-Independent T Cell Development and Effector Function In Vivo

Transgenic Expression of CTLA-4 Controls Lymphoproliferation in IL-2-Deficient Mice

Differential role of IL‐2R signaling for CD8+ T cell responses in acute and chronic viral infections

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Differential role of IL‐2R signaling for CD8⁺ T cell responses in acute and chronic viral infections