Co-stimulatory members of the TNFR family: keys to effective T-cell immunity?

Croft, Michael

doi:10.1038/nri1148

Cited by 777 publications

(784 citation statements)

References 129 publications

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“…TRAF2, TRAF3) and activation of different pathways, such as PI3K, JNK and NF-KB, has been described for many of the co-stimulatory receptors, including CD27, OX40 and 4-1BB. 28,29 Thus although not naturally cross-linked by individual co-stimulatory ligands we propose that duokine-mediated clustering of different receptors results in potent activation of downstream signals of commonly used pathways.…”

Section: Discussionmentioning

confidence: 93%

Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

et al. 2018

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Co-stimulatory signals induced by ligands of the tumor necrosis factor superfamily (TNFSF) play a central role in T cell activation and have emerged as a promising strategy in cancer immunotherapy. Here, we established a novel class of bifunctional co-stimulatory fusion proteins with the aim to boost T cell activation at the level of T cell – antigen-presenting cell (APC) interaction. These novel dual-acting cytokine fusion proteins were created by connecting two different homotrimeric TNFSF ligands to form homotrimeric bifunctional molecules (Duokines) or by connecting single-chain derivatives of two different homotrimeric TNFSF with a single, flexible linker (single-chain Duokines, scDuokines). By linking the TNFSF ligands 4-1BBL, OX40L and CD27L in all possible combinations, cis-acting Duokines were generated that act on the same or adjacent T cells, while combining CD40L with 4-1BBL, OX40L and CD27L resulted in trans-acting Duokines acting simultaneously on APCs and T cells. In vitro, co-stimulation of T cells was seen for cis- and trans-acting Duokines and scDuokines in an antigen-independent as well as antigen-specific setting. Trans-acting molecules furthermore activated B cells, which represent a subclass of APCs. In a pilot experiment using the syngeneic B16-FAP mouse tumor model scDuokines displayed antitumoral activity in vivo in combination with a primary T cell-activating bispecific antibody, evident from reduced number of lung metastasis compared to the antibody-only treated group. Our data show that the bifunctional, co-stimulatory duokines are capable to enhance T cell-mediated anti-tumor immune responses, suggesting that they can serve as a new class of immuno-stimulatory molecules for use in cancer immunotherapy strategies.

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Section: Discussionmentioning

confidence: 93%

Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

et al. 2018

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“…LIGHT also engages the herpes virus entry mediator (HVEM; TNFRS14). The LIGHT-HVEM interaction appears to induce a positive signal during T cell activation, as do its TNFR paralogs (e.g., 4-1BB, OX40, CD27) [15].…”

Section: Regulation Of DC Homeostasis By the Tnfr Superfamilymentioning

confidence: 97%

The TNF receptor and Ig superfamily members form an integrated signaling circuit controlling dendritic cell homeostasis

Trez

Ware

2008

Cytokine & Growth Factor Reviews

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Dendritic cells (DC) constitute the most potent antigen presenting cells of the immune system, playing a key role bridging innate and adaptive immune responses. Specialized DC subsets differ depending on their origin, tissue location and the influence of trophic factors, the latter remain to be fully understood. Stromal cell and myeloid-associated Lymphotoxin-β receptor (LTβR) signaling is required for the local proliferation of lymphoid tissue DC. This review focuses the LTβR signaling cascade as a crucial positive trophic signal in the homeostasis of DC subsets. The noncanonical coreceptor pathway comprised of the Immunoglobulin (Ig) superfamily member, B and T lymphocyte attenuator (BTLA) and TNFR superfamily member, Herpesvirus entry mediator (HVEM) counter regulates the trophic signaling by LTβR. Together both pathways form an integrated signaling circuit achieving homeostasis of DC subsets.Keywords dendritic cells; homeostasis; TNF superfamily; cosignaling; lymphotoxin; herpesvirus entry mediator Dendritic CellsDendritic cells (DC) originate from hematopoietic precursors and can be divided in several subsets depending on their anatomical location, surface phenotype and function. For example, two broad classes of DC are the peripheral migratory DC and the lymphoid tissue-resident DC [1]. The migratory DC, i.e. the dermal DC and Langerhans cells, can be considered as sentinels of the immune system as they form a sensing barrier in peripheral tissues at the interface with environment. The lymphoid tissue-resident DC include the splenic and thymic DC.Dendritic cells are specialized in the capture, transport, processing and presentation of antigens. In the presence of a microbial stimulus, these steps are associated with further DC differentiation (maturation) characterized by upregulation of costimulatory and major histocompatibility complex (MHC) molecules. As DC become activated they migrate to or Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Both spleen and lymph node lymphoid tissue-resident DC possess a half-life of about three days. Despite their rapid turnover, little is known about the factors controlling immediate precursors and homeostasis in vivo. In earlier studies, CD8α expression was used to distinguish between "lymphoid" and "myeloid" DC. However, more recent experiments showed that different DC subsets could differentiate from both lymphoid and myeloid precursors [6,7]. CD8α marker remains very useful to discriminate between subsets, but no longer defines a subset origin. Recently, the group of Shortman provided in vivo and in vitro evidence fo...

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“…They also act as costimulatory molecules involved in the bi-directional signaling in and out of T cells. Costimulatory signals may perform several functions, such as augmenting production of interleukin (IL)-2 or the archetypal growth factor, promoting cell cycle progression, inducing effector cytokine production, such as those of the Th1 and Th2 type, suppressing cell death by altering bcl-2 and caspase protein function, and enhancing memory T cell development (4,5). Advances in our understanding of T cell costimulatory molecules have provided a vast array of novel approaches in preventing autoimmune, infectious, inflammatory, and tumorous diseases (6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%