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

So, Takanori; Lee, Seung-Woo; Croft, Michael

doi:10.1016/j.cytogfr.2008.04.003

Cited by 119 publications

(101 citation statements)

References 62 publications

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“…46 On the contrary, these molecules as well as ICOS also facilitate the expansion of T reg cells. 36,45,47 B cells of aged BWF1 mice, however, did not show significant expression of ligands for these co-stimulatory molecules (data not shown). This observation implies that reversal of the suppression, if any, might take place through the other pathway(s).…”

Section: Discussionmentioning

confidence: 99%

“…[42][43][44] OX40 and 4-1BB magnify the T-cell response through induction of the proliferation of conventional T cells and inhibition of T reg cell-mediated immune suppression. 37,45 The ICOS-mediated signal is essential for the induction of follicular helper T cells, thus it functions as an enhancer of B-cell response. 46 On the contrary, these molecules as well as ICOS also facilitate the expansion of T reg cells.…”

Section: Discussionmentioning

confidence: 99%

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Increased Foxp3+ CD4+ Regulatory T Cells with Intact Suppressive Activity but Altered Cellular Localization in Murine Lupus

Abe

Ueha

Suzuki

et al. 2008

The American Journal of Pathology

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Foxp3 ؉ CD4 ؉ regulatory T (T reg ) cells play a pivotal role in the maintenance of dominant self tolerance. Understanding how the failures of immune control by T reg cells are involved in autoimmune diseases is important for the development of effective immunotherapies. In the present study, we analyzed the characteristics of endogenous T reg cells in (NZB ؋ NZW) F1 (BWF1) mice, a murine model of systemic lupus erythematosus. Unexpectedly, T reg number and frequency in aged BWF1 mice with developing lupus nephritis were increased, not decreased, and in vitro suppressive activity in lymphoid organs was intact. In addition, T reg cells trafficked to target organs because cells were present in the kidney and lung. T reg cells of aged BWF1 mice exhibited altered localization within lymph organs, however, and an altered phenotype, with higher expression levels of chemokine receptors and activation markers, suggesting a highly activated cellular state. Notably, the expression levels of costimulatory molecules were also markedly enhanced in the T reg cells of aged BWF1 mice. Furthermore, T reg cells of BWF1 mice did not show any suppressive effects on antibody production in vitro. Taken together, we conclude that T reg cells in BWF1 mice are not predisposed to functional incompetence but rather are present in a highly activated state. Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology characterized by a massive production of autoantibodies against various nuclear antigens. The deposit of immune complexes in the target organs, ie, skin, kidney, lung, joints, and central nervous system, is thought to cause fatal dysfunction of the body system. (NZB ϫ NZW) F1 (BWF1) is a mouse strain that has been widely used as a model for SLE since the 1960s. These mice spontaneously develop severe autoimmune disease highly resembling human SLE in terms of serological and hematological abnormalities, and severe nephritis accompanying massive production of antinuclear antibodies. 1 Reconstitution of SCID (severe combined immunodeficiency) mice with cultured pre-B cells of BWF1 mice recapitulates many symptoms of the disease of BWF1 mice. Cultured pre-B cells alone, however, are not sufficient to fully reproduce the disease. 2 These data suggest that cellular subset(s) in addition to B cells are necessary for the development of the lupus-like syndrome of BWF1 mice, although abnormalities of the immune system predominantly lie within B cells. One of the possible candidates is CD4 ϩ T cells, because depletion of CD4 ϩ T cells with anti-CD4 antibody from 5 months old, slightly before the disease onset, prevents the development of the disease. 3,4 CD4 ϩ T cells are, therefore, also required for the development of the disease in BWF1 mice, possibly by providing help for the production of high-affinity autoantibodies.Studies in this decade have clearly shown the key roles of naturally occurring regulatory T (T reg ) cells in the maintenance of dominant self tolerance of the immune system. 5 T reg cells in normal mi...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Increased Foxp3+ CD4+ Regulatory T Cells with Intact Suppressive Activity but Altered Cellular Localization in Murine Lupus

Abe

Ueha

Suzuki

et al. 2008

The American Journal of Pathology

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“…Second, another set of Treg cell genes (circle 2) was associated with both the suppression of zone A (blue) genes and induction of D (orange) genes, suggesting that these Treg cell genes counteract against the induction and suppression of the Teff cell genes triggered through CD3 stimulation. Third, the largest group of Treg genes (circle 3) was exclusively associated to suppress the zone A genes, which included CD101 tested in this study, and some key Treg cell genes such as HLADR, TNFRSF9, and DUSP4 (14,20,34). This analysis suggests that Treg cells may use two major sets of genes to modulate Teff gene responses in vitro: one counteracting Teff cell activation (zone A and D) and the other inducing an autoinhibitory mechanism (zone C).…”

Section: Interactions Between Treg Cell and Teff Cell Genesmentioning

confidence: 99%

Diverse Gene Expression in Human Regulatory T Cell Subsets Uncovers Connection between Regulatory T Cell Genes and Suppressive Function

Hua

Davis

Hill

et al. 2015

The Journal of Immunology

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Regulatory T (Treg) cells have a critical role in the control of immunity, and their diverse subpopulations may allow adaptation to different types of immune responses. In this study, we analyzed human Treg cell subpopulations in the peripheral blood by performing genome-wide expression profiling of 40 Treg cell subsets from healthy donors. We found that the human peripheral blood Treg cell population is comprised of five major genomic subgroups, represented by 16 tractable subsets with a particular cell surface phenotype. These subsets possess a range of suppressive function and cytokine secretion and can exert a genomic footprint on target effector T (Teff) cells. Correlation analysis of variability in gene expression in the subsets identified several cell surface molecules associated with Treg suppressive function, and pharmacological interrogation revealed a set of genes having causative effect. The five genomic subgroups of Treg cells imposed a preserved pattern of gene expression on Teff cells, with a varying degree of genes being suppressed or induced. Notably, there was a cluster of genes induced by Treg cells that bolstered an autoinhibitory effect in Teff cells, and this induction appears to be governed by a different set of genes than ones involved in counteracting Teff activation. Our work shows an example of exploiting the diversity within human Treg cell subpopulations to dissect Treg cell biology.

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“…In addition to costimulatory receptors of the CD28 family, several members of the TNFR superfamily, to date OX-40, CD27, CD30, 4-1BB, Herpes virus entry mediator, glucocorticoidinduced TNFR and TNFRII, have been shown also to exert costimulatory effects on T cells. [2][3][4][5][6][7][8][9][10]14,17 In this study, we investigated the role of TNFRI in T-cell activation in response to TCR stimulation. Here, we show that TNFRI is required for initial T-cell activation after TCR engagement.…”

Section: Discussionmentioning

confidence: 99%

“…Costimulatory signals from CD28 and CD27 are important for the initiation of T-cell activation, lowering the threshold of TCR activation by enhancing proliferation and interleukin 2 (IL-2) production, while TNFR family members participate in the control of effector T-cell differentiation [4][5][6][7][8][9][10] and survival. 3 Enhancement of TCR-or mitogen-induced T-cell proliferation and IL-2 receptor a-chain (CD25) expression was one of the first recognized functions of TNF.…”

mentioning

confidence: 99%

TNFRI is a positive T‐cell costimulatory molecule important for the timing of cytokine responses

et al. 2010

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Tumor necrosis factor (TNF)-and TNF receptor I (TNFRI)-deficient mice are resistant to initiation and show delayed resolution of disease in paradigms of autoimmune disease, but the contribution of TNF/TNFRI signaling to T-cell activation and effector responses has not been determined. In this study, we investigated the role of TNFRI in T-cell receptor (TCR)-mediated T-cell activation in vitro and in vivo using CD3 + -enriched primary T cells and mice deficient in TNFRI. Following TCR engagement, TNFRI knockout (KO) T cells showed significantly delayed proliferation, cell division, upregulation of interleukin 2 (IL-2) and IL-2 receptor a chain (CD25) mRNA and cell-surface expression of CD25 compared with wild-type (WT) cells. Thus, WT and TNFRI KO cells showed equivalent proliferation peaks at 48 and 72 h, respectively. TNFRI KO mice also developed a defective primary T-cell response to ovalbumin and an acute contact hypersensitivity response to oxazolone (4-ethoxymethylene-2-phenyl-2-oxazolin-5-one). However, TNFRI KO splenocytes that were stimulated by TCR engagement in vitro for 96 h produced significantly higher intracellular levels of interferon-c (IFN-c), IL-2 and TNF-a, but not IL-17, compared with WT cells, in correlation with their relatively higher proliferation rate at this time point. Further, TCR-stimulated CD3 + -enriched TNFRI KO T cells showed similarly higher production and secretion of IFN-c and IL-2 compared with WT, suggesting that TNFRI-mediated cytokine regulation might involve a T-cell autonomous effect. Our results show a novel role for TNFRI as a positive T-cell costimulatory molecule that is important for timely T-cell activation and effector cytokine production and the development of primary immune responses in mice. Keywords: TNFRI knockout mice; contact hypersensitivity reaction; TCR signaling Once a CD4 + or CD8 + T cell has received an antigen (Ag)-specific signal from the T-cell receptor (TCR), additional Ag-independent, costimulatory signals from receptors belonging to the CD28 1 and tumor necrosis factor receptor (TNFR) 2,3 families deliver positive and negative signals that are critical for shaping, sustaining and terminating the immune response and for limiting the development of autoimmunity. Costimulatory signals from CD28 and CD27 are important for the initiation of T-cell activation, lowering the threshold of TCR activation by enhancing proliferation and interleukin 2 (IL-2) production, while TNFR family members participate in the control of effector T-cell differentiation 4-10 and survival. 3 Enhancement of TCR-or mitogen-induced T-cell proliferation and IL-2 receptor a-chain (CD25) expression was one of the first recognized functions of TNF. 11,12 Resting T cells express both of the TNF receptors, TNFRI (p55TNFR) and TNFRII (p75TNFR), and their expression is further upregulated after activation. 13,14 The selective stimulation of TNFRII induced proliferation in mouse and human thymocytes and in peripheral human T cells, 15,16 and studies in TNFRII knockout (KO) mice showe...

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

Cited by 119 publications

References 62 publications

Increased Foxp3+ CD4+ Regulatory T Cells with Intact Suppressive Activity but Altered Cellular Localization in Murine Lupus

Increased Foxp3+ CD4+ Regulatory T Cells with Intact Suppressive Activity but Altered Cellular Localization in Murine Lupus

Diverse Gene Expression in Human Regulatory T Cell Subsets Uncovers Connection between Regulatory T Cell Genes and Suppressive Function

TNFRI is a positive T‐cell costimulatory molecule important for the timing of cytokine responses

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