Signals from OX40 regulate nuclear factor of activated T cells c1 and T cell helper 2 lineage commitment

So, Takanori; Song, Jianxun; Sugie, Katsuji; Croft, Michael

doi:10.1073/pnas.0600205103

Cited by 104 publications

(90 citation statements)

References 52 publications

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“…S5A). Both OX40L-OX40 interactions and TSLP play key roles in promoting Th2 immunity (26,27). Therefore, we asked whether these molecules could mediate Nod-dependent Th2 differentiation.…”

Section: Ligand Sensing In the Stromal Compartment Is Necessary Formentioning

confidence: 99%

Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation

Magalhães¹,

Rubino

Travassos³

et al. 2011

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

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Although a number of studies have examined the development of T-helper cell type 2 (Th2) immunity in different settings, the mechanisms underlying the initiation of this arm of adaptive immunity are not well understood. We exploited the fact that immunization with antigen plus either nucleotide-binding oligomerization domain-containing proteins 1 (Nod1) or 2 (Nod2) agonists drives Th2 induction to understand how these pattern-recognition receptors mediate the development of systemic Th2 immune responses. Here, we show in bone-marrow chimeric mice that Nod1 and Nod2 expression within the stromal compartment is necessary for priming of effector CD4 + Th2 responses and specific IgG1 antibodies. In contrast, sensing of these ligands by dendritic cells was not sufficient to induce Th2 immunity, although these cells contribute to the response. Moreover, we determined that CD11c + cells were the critical antigen-presenting cells, whereas basophils and B cells did not affect the capacity of Nod ligands to induce CD4 + Th2 effector function. Finally, we found that full Th2 induction upon Nod1 and Nod2 activation was dependent on both thymic stromal lymphopoietin production by the stromal cells and the up-regulation of the costimulatory molecule, OX40 ligand, on dendritic cells. This study provides in vivo evidence of how systemic Th2 immunity is induced in the context of Nod stimulation. Such understanding will influence the rational design of therapeutics that could reprogram the immune system during an active Th1–mediated disease, such as Crohn's disease.

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“…S5A). Both OX40L-OX40 interactions and TSLP play key roles in promoting Th2 immunity (26,27). Therefore, we asked whether these molecules could mediate Nod-dependent Th2 differentiation.…”

Section: Ligand Sensing In the Stromal Compartment Is Necessary Formentioning

confidence: 99%

Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation

Magalhães¹,

Rubino

Travassos³

et al. 2011

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

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“…Results showing OX40 can concomitantly promote effector T cell generation while antagonizing the differentiation of iTregs [2,31,38] additionally indicate that cytokines produced from OX40-triggered T cells may be important for suppressing Foxp3, essentially providing an indirect route for antagonizing Treg generation. Th1, Th2, Th17, and iTreg populations are all derived from naïve CD4 T cells and promoted in a cytokine-dependent manner through specific lineage-specific transcription factors, T-bet, GATA-3, RORγt, and Foxp3, respectively.…”

Section: Ox40 Antagonizes Induction Of Foxp3 In Naïve Cd4 T Cellsmentioning

confidence: 96%

Immune regulation and control of regulatory T cells by OX40 and 4-1BB

Lee

Croft

2008

Cytokine & Growth Factor Reviews

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119

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The TNFR family members OX40 (CD134) and 4-1BB (CD137) have been found to play major roles as costimulatory receptors for both CD4 and CD8 T cells. In particular, in many situations, they can control proliferation, survival, and cytokine production, and hence are thought to dictate accumulation of protective T cells during anti-viral and anti-tumor responses and pathogenic T cells during autoimmune reactions. As opposed to simply controlling the activity of naïve, effector, and memory T cells, recent data have suggested that both molecules are also instrumental in controlling the generation and activity of so-called regulatory or suppressor T cells (Treg), perhaps in both positive and negative manners. Part of the action on Treg might function to further promote protective or pathogenic T cells, but alternate activities of OX40 and 4-1BB on Treg are also being described that suggest there might be control by these molecules at multiple levels that will alter the biological outcome when these receptors are ligated. This review specifically focuses on recent studies of regulatory T cells, and regulatory or suppressive activity, that are modulated by OX40 or 4-1BB.

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“…OVA 323-339 -specific cytokine-producing cells were enumerated using the ELISPOT assay, as previously described (11). Peptide-specific cytokine spots were enumerated by subtracting the spots produced in wells without Ag from those produced in the presence of 0.3 mM OVA 323-339 peptide.…”

Section: Elispotmentioning

confidence: 99%

“…The production of IL-4 is critical for the substantial generation of Th2 cells. Studies have identified basophils (7,8) and NKT cells (9) as the critical source of IL-4, whereas other studies demonstrate that naive CD4 T cells themselves produce sufficient levels of IL-4 for the development of Th2 cells (10)(11)(12). Yet other studies have implicated various costimulatory molecule receptors, such as OX-40 (13,14), ICOS (15), and CD28 (16)(17)(18)(19), in the differential development of Th2 over Th1 cells.…”

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confidence: 99%

The Number of Responding CD4 T Cells and the Dose of Antigen Conjointly Determine the Th1/Th2 Phenotype by Modulating B7/CD28 Interactions

Rudulier

McKinstry

Al‐Yassin

et al. 2014

The Journal of Immunology

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Our previous in vivo studies show that both the amount of Ag and the number of available naive CD4 T cells affect the Th1/Th2 phenotype of the effector CD4 T cells generated. We examined how the number of OVA-specific CD4 TCR transgenic T cells affects the Th1/Th2 phenotype of anti-SRBC CD4 T cells generated in vivo upon immunization with different amounts of OVA-SRBC. Our observations show that a greater number of Ag-dependent CD4 T cell interactions are required to generate Th2 than Th1 cells. We established an in vitro system that recapitulates our main in vivo findings to more readily analyze the underlying mechanism. The in vitro generation of Th2 cells depends, as in vivo, upon both the number of responding CD4 T cells and the amount of Ag. We demonstrate, using agonostic/antagonistic Abs to various costimulatory molecules or their receptors, that the greater number of CD4 T cell interactions, required to generate Th2 over Th1 cells, does not involve CD40, OX40, or ICOS costimulation, but does involve B7/CD28 interactions. A comparison of the level of expression of B7 molecules by APC and CD4 T cells, under different conditions resulting in the substantial generation of Th1 and Th2 cells, leads us to propose that the critical CD28/B7 interactions, required to generate Th2 cells, may directly occur between CD4 T cells engaged with the same B cell acting as an APC.

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Signals from OX40 regulate nuclear factor of activated T cells c1 and T cell helper 2 lineage commitment

Cited by 104 publications

References 52 publications

Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation

Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation

Immune regulation and control of regulatory T cells by OX40 and 4-1BB

The Number of Responding CD4 T Cells and the Dose of Antigen Conjointly Determine the Th1/Th2 Phenotype by Modulating B7/CD28 Interactions

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