The importance of co‐stimulation in the orchestration of T helper cell differentiation

Coquet, Jonathan M.; Rausch, Lisa; Borst, Jannie

doi:10.1038/icb.2015.45

Cited by 30 publications

(22 citation statements)

References 115 publications

(230 reference statements)

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“…S5B), thus it is unlikely that Th1 responses are absolutely TNFR2-dependent. In addition to TCR signaling, co-stimulation is required for the priming and differentiation of T helper cells46. In our in vitro Th1 differentiation assay, the cells were stimulated with anti-CD3 as well as anti-CD28 Abs.…”

Section: Discussionmentioning

confidence: 99%

TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis

Chen

Nie

Xiao

et al. 2016

Sci Rep

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There is now compelling evidence that TNFR2 is constitutively expressed on CD4+ Foxp3+ regulatory T cells (Tregs) and TNF-TNFR2 interaction is critical for the activation, expansion and functional stability of Tregs. However, we showed that the expression of TNFR2 was also up-regulated on CD4+ Foxp3− effector T cells (Teffs) upon TCR stimulation. In order to define the role of TNFR2 in the pathogenic CD4 T cells, we compared the effect of transferred naïve CD4 cells from WT mice and TNFR2−/− mice into Rag 1−/− recipients. Transfer of TNFR2-deficient Teff cells failed to induce full-fledged colitis, unlike WT Teffs. This was due to defective proliferative expansion of TNFR2-deficient Teff cells in the lymphopenic mice, as well as their reduced capacity to express proinflammatory Th1 cytokine on a per cell basis. In vitro, the proliferative response of TNFR2 deficient naïve CD4 cells to anti-CD3 stimulation was markedly decreased as compared with that of WT naïve CD4 cells. The hypoproliferative response of TNFR2-deficient Teff cells to TCR stimulation was associated with an increased ratio of p100/p52, providing a mechanistic basis for our findings. Therefore, this study clearly indicates that TNFR2 is important for the proliferative expansion of pathogenic Teff cells.

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Section: Discussionmentioning

confidence: 99%

TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis

Chen

Nie

Xiao

et al. 2016

Sci Rep

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“…This could be either through hormone receptor binding to the CD1d promoter or through hormonal influence on the cytokine environment and antigen presenting cell activation altering interaction of macrophage/dendritic cells with the innate T cell subsets. Estrogen enhances dendritic cell maturation and antigen presentation resulting in increased MHC and accessory molecule expression, which may lead to stronger T cell-APC interactions [50]. Also sex hormones affect TLR expression and signaling.…”

Section: Discussionmentioning

confidence: 99%

ERÃÂ² and ERÃÂ± Differentially Regulate NKT and VÃÂ³4+ T-cell Activation and T-regulatory Cell Response in Coxsackievirus B3 Infected Mice

Huber¹

2015

J Clin Cell Immunol

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Objectives Coxsackievirus B3 (CVB3) induced myocarditis is sex dependent with males developing more severe disease than females. Previous studies had shown that sex-associated hormones determine the sex bias with testosterone and progesterone promoting myocarditis while estrogen (E2) is protective. There are two major estrogen receptors: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). The goal of the current study was to determine the relative role of these receptors to myocarditis susceptibility and the mechanism of their action. Methods Female C57Bl/6 wild-type mice and C57Bl/6 mice deficient in ERα, or ERβ were infected intraperitoneally with 102 plaque forming units CVB3. After 7 days, hearts were evaluated for virus titers by plaque forming assay and myocardial inflammation. Lymphoid cells either from the spleen or infiltrating the heart were characterized by labeling with antibodies including CD4, CD25, FoxP3, IFNγ, IL-4, CD11b, CD1d, Vγ4, TCRβ, or with CD1d-tetramer and evaluated by flow cytometry. To confirm that signaling through distinct estrogen receptors controlled myocarditis susceptibility and T-regulatory cell response, male C57Bl/6 mice were treated with the ERα-specific agonist, propyl pyrazole triol (PPT), ERβ agonist, diarylpropionitrile (DPN), or 17-β-estradiol (E2) as a non-specific estrogen receptor agonist. Results Myocarditis, cardiac virus titers, and CD4+ Th1 (IFNγ) bias were increased in infected ERαKO and decreased in infected ERβKO mice compared to C57Bl/6 controls. CD4+Th1 bias and myocarditis severity correlated inversely with numbers of CD4+CD25+FoxP3+ T regulatory cells which were decreased in ERαKO and increased in ERβKO mice. Increased T-regulatory cells corresponded to a preferential activation of natural killer T (NKT) cells in ERβKO mice. Male C57Bl/6 mice treated with DPN showed increased myocarditis while those treated with PPT and E2 showed decreased myocarditis corresponding to either decreased (DPN) or increased (PPT/E2) T-regulatory cell responses in male C57Bl/6 mice. DPN and PPT treatment had no effect on T-regulatory cell responses in NKT KO or γδKO mice. Conclusion These results demonstrate that ERα and ERβ both modulated CVB3 myocarditis susceptibility but in opposite directions and that their predominant effect is mediated through their ability to alter NKT and Vγ4+ innate T cell responses in the infected host. It is these innate T cells which positively or negatively modulate T-regulatory cell responses.

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“…On the search for cognate Ags naïve T cells scan about 100 DCs per hour . When a T cell recognizes a peptide presented in the context of MHC and co‐stimulatory molecules on a DC, T cells interrupt their migration path to form an IS with the DC, resulting in T cell activation, proliferation, and differentiation . The outcome of T cell activation depends on the context of Ag recognition and is largely controlled by various co‐stimulatory molecules.…”

Section: Chemokine Receptors As Co‐stimulatory Molecules For Efficienmentioning

confidence: 99%

Beyond migration—Chemokines in lymphocyte priming, differentiation, and modulating effector functions

Laufer

Legler

2018

Journal of Leukocyte Biology

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Chemokines and their receptors coordinate the positioning of leukocytes, and lymphocytes in particular, in space and time. Discrete lymphocyte subsets, depending on their activation and differentiation status, express various sets of chemokine receptors to be recruited to distinct tissues. Thus, the network of chemokines and their receptors ensures the correct localization of specialized lymphocyte subsets within the appropriate microenvironment enabling them to search for cognate antigens, to become activated, and to fulfill their effector functions. The chemokine system therefore is vital for the initiation as well as the regulation of immune responses to protect the body from pathogens while maintaining tolerance towards self. Besides the well investigated function of orchestrating directed cell migration, chemokines additionally act on lymphocytes in multiple ways to shape immune responses. In this review, we highlight and discuss the role of chemokines and chemokine receptors in controlling cell-to-cell contacts required for lymphocyte arrest on endothelial cells and immunological synapse formation, in lymphocyte priming and differentiation, survival, as well as in modulating effector functions.

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The importance of co‐stimulation in the orchestration of T helper cell differentiation

Cited by 30 publications

References 115 publications

TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis

TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis

ERÃÂ² and ERÃÂ± Differentially Regulate NKT and VÃÂ³4+ T-cell Activation and T-regulatory Cell Response in Coxsackievirus B3 Infected Mice

Beyond migration—Chemokines in lymphocyte priming, differentiation, and modulating effector functions

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The importance of co‐stimulation in the orchestration of T helper cell differentiation

Cited by 30 publications

References 115 publications

TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis

TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis

ERÃÂ² and ERÃÂ± Differentially Regulate NKT and VÃÂ³4+ T-cell Activation and T-regulatory Cell Response in Coxsackievirus B3 Infected Mice

Beyond migration—Chemokines in lymphocyte priming, differentiation, and modulating effector functions

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Product

Resources

About

ERÃÂ² and ERÃÂ± Differentially Regulate NKT and VÃÂ³4+ T-cell Activation and T-regulatory Cell Response in Coxsackievirus B3 Infected Mice