Identification of a human OX-40 ligand, a costimulator of CD4+ T cells with homology to tumor necrosis factor.

Godfrey, Wayne R.; Fagnoni, F F; Harara, M A; Buck, David C.; Engleman, Edgar G.

doi:10.1084/jem.180.2.757

Cited by 257 publications

(162 citation statements)

References 27 publications

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“…The function of this co-stimulatory receptor has mostly been studied in CD4 T cells, but has also been shown to enhance CD8 T cell responses [43,44]. As OX40 ligand is expressed by B cells, the CXCR5 + CD8 T cells could be positively regulated by B cells in the follicle via this receptor pair [45]. One could also speculate that CD8 T cells may use CD27-CD70-mediated interaction with B cells to increase effector CD8 T cell pool size and increase IFN-c production [46][47][48].…”

Section: Discussionmentioning

confidence: 99%

CXCR5⁺ CCR7^– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles

et al. 2007

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Naive and central memory CD8 T cells use CCR7 to recirculate through T cell zones of secondary lymphoid organs where they can encounter antigen. Here we describe a subset of human CD8 T cells expressing CXCR5 which enables homing in response to CXCL13 produced within B cell follicles. CXCR5 + CD8 T cells were found in tonsil B cell follicles, and isolated cells migrated towards CXCL13 in vitro. They expressed CD27, CD28, CD45RO, CD69, and were CD7 low , and produced IFN-c and granzyme A but lacked perforin, a functional profile suggesting that these cells are early effector memory cells in the context of contemporary T cell differentiation models. Receptors important in the interaction with B cells, including CD70, OX40 and ICOS, were induced upon activation, and CXCR5 + CD8 T cells could to some extent support survival and IgG production in tonsil B cells. Furthermore, CXCR5 + CD8 T cells expressed CCR5 but no CCR7, suggesting a migration pattern distinct from that of follicular CD4 T cells. The finding that a subset of early effector memory CD8 T cells use CXCR5 to locate to B cell follicles indicates that MHC class I-restricted CD8 T cells are part of the follicular T cell population. IntroductionCD8 T cells are lymphocytes of the adaptive immune system which recognize viral and bacterial peptides presented by MHC class I molecules and are indispensable in the control of many intracellular infections [1]. When appropriately stimulated by antigen presented by dendritic cells (DC) in secondary lymphoid tissues, they proliferate vigorously, become effector cells, and upon resolution of infection a small population of antigen-specific CD8 T cells are maintained as long-lived memory cells [2][3][4]. A primary effector mechanism of CD8 T cells is the killing of infected cells via the targeted release of the lytic effector molecules perforin and granzymes, and via expression of death receptors. However, there is significant functional heterogeneity in CD8 T cells and they are also efficient in producing anti-viral and pro-inflammatory cytokines [5][6][7][8]. The effector mechanisms used may depend on the pathogen and on the type of cell or tissue that is infected [8].CD8 T cell responses involve the differentiation of naive T cells into distinct types of effector and memory cells [2, 3,9]. One approach to analyse a T cell response is to examine the expression of receptors that mediate homing of T cells, such as CD62L, which binds to glycosylation-dependent cell adhesion molecule 1 on [4,20,21]. CXCR5 is a chemokine receptor which is expressed on all B cells and on specialized subsets of DC and T cells [22]. It has only one known ligand, the chemokine CXCL13, mainly produced by stromal cells and follicular DC within B cell follicles [23][24][25]. CXCR5 + CD4 T cells, known as follicular homing T helper cells, are found in B cell follicles and contribute to the generation of effective humoral immune responses by supporting antibody production and isotype class switching [26,27]. However, some of the processes and mec...

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Section: Discussionmentioning

confidence: 99%

CXCR5⁺ CCR7^– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles

et al. 2007

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“…In addition to LIGHT, several members of the TNFR superfamily, including 4-1BB and OX-40, have been shown to costimulate T cell growth and induce TNFR-associated factor binding and NF-B activation (9,10,36). However, the expression and function of these molecules appear to have individual characteristics.…”

Section: Discussionmentioning

confidence: 99%

“…However, the expression and function of these molecules appear to have individual characteristics. For example, 4-1BB engagement preferentially activates CD8 ϩ T cells compared with CD4 ϩ T cells (10), whereas OX-40 plays a predominant role on CD4 ϩ T cells because of its limited expression on CD4 ϩ T cells (9). In addition, the OX-40 costimulation polarizes T cells toward Th2-type responses (37), whereas the LIGHT costimulates T cells to produce IFN-␥ but not IL-4 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…For example, 4-1BB and OX-40 can costimulate T cell growth and affect the differentiation of subsets of Th cells (9,10). Administration of anti-4-1BB mAbs elicits curative antitumor immune responses against established tumors in several mouse models (4), indicating that costimulatory functions of the TNF superfamily can be manipulated toward therapeutic benefit.…”

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LIGHT, a TNF-Like Molecule, Costimulates T Cell Proliferation and Is Required for Dendritic Cell-Mediated Allogeneic T Cell Response

Tamada

Shimozaki

Chapoval

et al. 2000

The Journal of Immunology

365

335

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LIGHT is a recently identified member of the TNF superfamily and its receptors, herpesvirus entry mediator and lymphotoxin β receptor, are found in T cells and stromal cells. In this study, we demonstrate that LIGHT is selectively expressed on immature dendritic cells (DCs) generated from human PBMCs. In contrast, LIGHT is not detectable in DCs either freshly isolated from PBMCs or rendered mature in vitro by LPS treatment. Blockade of LIGHT by its soluble receptors, lymphotoxin β receptor-Ig or HVEM-Ig, inhibits the induction of DC-mediated primary allogeneic T cell response. Furthermore, engagement of LIGHT costimulates human T cell proliferation, amplifies the NF-κB signaling pathway, and preferentially induces the production of IFN-γ, but not IL-4, in the presence of an antigenic signal. Our results suggest that LIGHT is a costimulatory molecule involved in DC-mediated cellular immune responses.

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“…Furthermore, it can be induced by TCR signaling in the absence of other costimulatory signals (7). Its ligand, OX40 ligand (OX40L), 2 has homology to TNF, is expressed by APCs, and provides a costimulatory signal to CD4 ϩ T cells (4,8,9). The importance of OX40 costimulation is revealed in OX40-and OX40L-deficient mice in which CD4 ϩ T cell responses are abrogated (8, 10 -13).…”

Section: O Ptimal Activation Of Naive T Cells Requires Two Signalsmentioning

confidence: 99%

OX40 Ligation on Activated T Cells Enhances the Control ofCryptococcus neoformansand Reduces Pulmonary Eosinophilia

Humphreys

Edwards

Walzl

et al. 2003

The Journal of Immunology

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Pulmonary eosinophilia induced in C57BL/6 mice after Cryptococcus neoformans infection is driven by CD4+ Th2 cells. The immunological mechanisms that protect against eosinophilia are not fully understood. Interaction of OX40 (CD134) and its ligand, OX40L, has been implicated in T cell activation and cell migration. Unlike CD28, OX40 is only expressed on T cells 1–2 days after Ag activation. Manipulation of this pathway would therefore target recently activated T cells, leaving the naive repertoire unaffected. In this study, we show that engagement of OX40 by an OX40L:Ig fusion protein drives IFN-γ production by CD4+ T cells and reduces eosinophilia and C. neoformans burden in the lung. Using gene-depleted mice, we show that reduction of eosinophilia and pathogen burden requires IL-12 and/or IFN-γ. C. neoformans infection itself only partially induces OX40L expression by APCs. Provision of exogenous OX40L reveals a critical role of this pathway in the prevention of C. neoformans-induced eosinophilia.

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Identification of a human OX-40 ligand, a costimulator of CD4+ T cells with homology to tumor necrosis factor.

Cited by 257 publications

References 27 publications

CXCR5⁺ CCR7^– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles

CXCR5⁺ CCR7^– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles

LIGHT, a TNF-Like Molecule, Costimulates T Cell Proliferation and Is Required for Dendritic Cell-Mediated Allogeneic T Cell Response

OX40 Ligation on Activated T Cells Enhances the Control ofCryptococcus neoformansand Reduces Pulmonary Eosinophilia

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Identification of a human OX-40 ligand, a costimulator of CD4+ T cells with homology to tumor necrosis factor.

Cited by 257 publications

References 27 publications

CXCR5+ CCR7– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles

CXCR5+ CCR7– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles

LIGHT, a TNF-Like Molecule, Costimulates T Cell Proliferation and Is Required for Dendritic Cell-Mediated Allogeneic T Cell Response

OX40 Ligation on Activated T Cells Enhances the Control ofCryptococcus neoformansand Reduces Pulmonary Eosinophilia

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CXCR5⁺ CCR7^– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles

CXCR5⁺ CCR7^– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles