Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice

Lin, Wen; Truong, Nga; Grossman, William; Haribhai, Dipica; Williams, Calvin B.; Wang, Jiafang; Martı́n, Martı́n G.; Chatila, Talal A.

doi:10.1016/j.jaci.2005.08.046

Cited by 206 publications

(184 citation statements)

References 32 publications

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“…Indeed, DC-and B-cell populations exhibit significant dysregulation and activation in the absence of Treg cells [3,20] and may therefore directly contribute to the differentiation and expansion of T FH cells in the absence of Treg cells. Further evidence to support DCs in the expansion of T FH cells, due to the absence of Treg cells, may relate to increased levels in IL-6 in Foxp3 DTR mice devoid of Treg cells (data not shown) and Foxp3-deficient mice [27]. IL-6 is an important soluble factor for the differentiation of T FH cells and is likely produced by DCs (reviewed in [28]).…”

Section: Discussionmentioning

confidence: 99%

Expansion of follicular helper T cells in the absence of Treg cells: Implications for loss of B‐cell anergy

et al. 2012

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The maintenance of B-cell anergy is essential to prevent the production of autoantibodies and autoimmunity. However, B-cell extrinsic mechanisms that regulate B-cell anergy remain poorly understood. We previously demonstrated that regulatory T (Treg) cells are necessary for the maintenance of B-cell anergy. We now show that in Treg-cell-deficient mice, helper T cells are necessary and sufficient for loss of B-cell tolerance/anergy. In addition, we show that the absence of Treg cells is associated with an increase in the proportion of CD4 + cells that express GL7 and correlated with an increase in germinal center follicular helper T (GC-T FH ) cells. These GC-T FH cells, but not those from Tregcell-sufficient hosts, were sufficient to drive antibody production by anergic B cells. We propose that a function of Treg cells is to prevent the expansion of T FH cells, especially GC-T FH cells, which support autoantibody production.Keywords: anergy r autoimmunity r B cells r T FH r Treg cells Supporting Information available online IntroductionThe production of autoantibodies due to loss of B-cell tolerance is central to the development of autoimmunity. Our understanding of the mechanisms that maintain B-cell tolerance, especially B-cell anergy, remains poorly defined. The absence of regulatory T (Treg) cells results in the development of IPEX, a fatal disease associated with the development of significant autoantibodies and autoimmunity [1,2]. The development of autoantibodies suggests that Treg cells play a key role in regulating B-cell tolerance, a statement supported by our previous study showing a role for Treg cells in the maintenance of B-cell anergy [3].Numerous signaling molecules have been identified whose absence prevents the establishment or maintenance of B-cell Correspondence: Dr. Stephen B. Gauld e-mail: sgauld@mcw.edu anergy at the intrinsic level (reviewed in [4]). However, our understanding of B-cell extrinsic mechanisms that regulate B-cell anergy remains poor. DCs have been shown to both positively and negatively regulate autoantibody production [5][6][7]. Helper T cells, or signals associated with T-cell help, appear to negatively regulate B-cell tolerance [8][9][10][11][12]. It remains unclear as to which helper T-cell populations can support autoantibody production.Follicular helper T (T FH ) cells are defined based on their expression of the chemokine receptor CXCR5, the transcription factor Bcl6, and play an essential role in providing help to B cells, promoting antibody production [13][14][15]. However, a role for T FH cells in the production of autoantibodies is less well defined. The expansion of T FH cells is known to be associated with a lupus-like disease in sanroque mice and CD4 + cells from the sanroque model support antichromatin autoantibody production in an adoptive transfer system [16,17]. A study by Simpson et al. [18] In our study, we use the Foxp3 DTR mouse model [20] to deplete the complete Treg-cell population in adult hosts and show that Treg cells are essential to prevent th...

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Section: Discussionmentioning

confidence: 99%

Expansion of follicular helper T cells in the absence of Treg cells: Implications for loss of B‐cell anergy

et al. 2012

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“…CD4 ϩ CD25 high Foxp3 ϩ Treg are potent suppressor of inflammatory processes leading to autoimmunity (38), allograft rejection (39), tumor growth (32), and chronic infection to parasites (40). With regards to Treg in allergic disorders, compelling evidence has been provided by Foxp3-deficient (scurfy) mice that reproduce the intense lymphoproliferation and allergic inflammation observed in patients with immune dysregulation polyendocrinopathy enteropathy-X-linked syndrome (41,42). Also relevant to allergic airway disease are results from clinical studies showing the ability of Treg to down-regulate Th2 cytokine production, albeit with an apparent inability to suppress the accompanying allergic airway inflammation (15,17).…”

Section: Discussionmentioning

confidence: 99%

Targeting of CD25 and Glucocorticoid-Induced TNF Receptor Family-Related Gene-Expressing T Cells Differentially Modulates Asthma Risk in Offspring of Asthmatic and Normal Mother Mice

Hubeau¹,

Apostolou

Kobzik

2007

The Journal of Immunology

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Immunological mechanisms leading to increased asthma susceptibility in early life remain obscure. In this study, we examined the effects of neonatal Ab treatments targeting T cell populations on the development of an asthma syndrome. We used a model of increased asthma susceptibility where offspring of asthmatic BALB/c mother mice are more prone (than normal pups) to develop the disease. Neonatal pretreatment of naive pups with mAb directed against the IL-2Rα chain (CD25), the costimulatory molecule glucocorticoid-induced TNFR family related gene, and the inhibitory molecule CTLA-4 elicited contrasting effects in offspring depending on the mother’s asthma status. Specifically, neonatal CD25high T cell depletion stimulated asthma susceptibility in normal offspring whereas it ameliorated the condition of pups born of asthmatic mothers. Conversely, glucocorticoid-induced TNFR family related gene ligation as a primary signal reduced the spleen cellularity and largely abrogated asthma susceptibility in asthma-prone offspring, without inducing disease in normal pups. Striking changes in Th1/Th2 cytokine levels, especially IL-4, followed mAb pretreatment and were consistent with the impact on asthma susceptibility. These results point to major differences in neonatal T cell population and responsiveness related to maternal asthma history. Interventions that temporarily remove and/or inactivate specific T cell subsets may therefore prove useful to attenuate early life asthma susceptibility and prevent the development of Th2-driven allergic airway disease.

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“…Indeed in humans, it has been reported that successful allergen immunotherapy is associated with the generation of IL-10-producing Tregs (43,44). However, the spontaneous development in Foxp3 mutant mice of allergic airway inflammation, hyperIgE and eosinophilia, in addition to several autoimmune syndromes, which are reversed by transfer in these mice of CD4 ϩ CD25 ϩ Tregs from wild type mice, provide evidence for an important role of naturally occurring CD4 ϩ CD25 ϩ Treg in the prevention of allergic diseases (34,45,46). In atopic subjects, a reduced numbers or defective suppressive function of CD4 ϩ CD25 ϩ Tregs has been demonstrated (47,48).…”

Section: Discussionmentioning

confidence: 99%

CD4+CD25+ Regulatory T Cells Specific for a Thymus-Expressed Antigen Prevent the Development of Anaphylaxis to Self

Scabeni

Lapilla²,

Musio³

et al. 2008

The Journal of Immunology

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A role for CD4+CD25+ regulatory T cells (Tregs) in the control of allergic diseases has been postulated. We developed a mouse model in which anaphylaxis is induced in SJL mice by immunization and challenge with the fragment of self myelin proteolipid protein (PLP)139–151, that is not expressed in the thymus, but not with fragment 178–191 of the same protein, that is expressed in the thymus. In this study, we show that resistance to anaphylaxis is associated with naturally occurring CD4+CD25+ Tregs specific for the self peptide expressed in the thymus. These cells increase Foxp3 expression upon Ag stimulation and suppress peptide-induced proliferation of CD4+CD25− effector T cells. Depletion of Tregs with anti-CD25 in vivo significantly diminished resistance to anaphylaxis to PLP178–191, suggesting an important role for CD4+CD25+ Tregs in preventing the development of allergic responses to this thymus-expressed peptide. These data indicate that naturally occurring CD4+CD25+ Tregs specific for a peptide expressed under physiological conditions in the thymus are able to suppress the development of a systemic allergic reaction to self.

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Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice

Cited by 206 publications

References 32 publications

Expansion of follicular helper T cells in the absence of Treg cells: Implications for loss of B‐cell anergy

Expansion of follicular helper T cells in the absence of Treg cells: Implications for loss of B‐cell anergy

Targeting of CD25 and Glucocorticoid-Induced TNF Receptor Family-Related Gene-Expressing T Cells Differentially Modulates Asthma Risk in Offspring of Asthmatic and Normal Mother Mice

CD4+CD25+ Regulatory T Cells Specific for a Thymus-Expressed Antigen Prevent the Development of Anaphylaxis to Self

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