Expression of lymphotoxin-αβ on antigen-specific T cells is required for DC function

Summers-Deluca, Leslie; McCarthy, Douglas D.; Cosovic, Bojana; Ward, Lesley A.; Lo, Chris; Scheu, Stefanie; Pfeffer, Klaus; Gommerman, Jennifer L.

doi:10.1084/jem.20061968

Cited by 56 publications

(72 citation statements)

References 37 publications

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“…Thus, thymic migration and localization of DCs may not rely on the CCR7-CCR7L chemotaxis and is unlikely to be a major contributor to impaired thymic negative selection in our Ltbr Ϫ/Ϫ mice. Whether our Ltbr Ϫ/Ϫ DCs have an intrinsic functional defect that contributes to the Ltbr Ϫ/Ϫ phenotype, as was suggested recently (38), remains an interesting question for future study.…”

Section: Discussionmentioning

confidence: 73%

Lymphotoxin β Receptor Is Required for the Migration and Selection of Autoreactive T Cells in Thymic Medulla

Zhu

Chin

Tumanov

et al. 2007

The Journal of Immunology

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How organ‐specific central tolerance is established and regulated has been an intriguing question. Lymphotoxin beta receptor (LTβR) deficiency is associated with autoimmune phenotypes characterized by humoral and cellular auto‐reactivity to peripheral organs. We sought to determine the role of LTβR in central tolerance of T cells directed at tissue‐restricted antigens. By tracing the development of OT‐I thymocytes in RIP‐mOVA transgenic mice on either Ltbr+/+ or Ltbr−/− background, we demonstrate that LTβR is necessary for thymic negative selection. LTβR deficiency resulted in a dramatic escape of “neo‐self” specific OT‐I cells that persist in circulation and lead to development of peri‐insulitis. When the underlying mechanism was further explored, we found interestingly that LTβR deficiency did not result in reduced thymic expression of mOVA. Instead, LTβR was revealed to control the expression of thymic medullary chemokines (SLC and ELC) which are required for thymocytes migration and negative selection in medulla as was confirmed by using SLC/ELC deficient mice. On the other hand, by tracing the development of OT‐II cells, we did not find any influence of LTβR deficiency on natural Treg positive selection, another arm of central tolerance. Thus, LTβR has been revealed to play an important role in thymic negative selection of organ‐specific thymocytes through thymic medullary chemokines regulation. This research was supported by grants from National Institutes of Health (NIH; AI062026, DK58897 to YXF)

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Section: Discussionmentioning

confidence: 73%

Lymphotoxin β Receptor Is Required for the Migration and Selection of Autoreactive T Cells in Thymic Medulla

Zhu

Chin

Tumanov

et al. 2007

The Journal of Immunology

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“…Their result also indicated that DC are dysfunctional without LTα 1 β 2 or CD40 ligand expression on antigen-activated T cells. However, signaling through either CD40 or LTβR restored DC function, suggesting that both pathways cooperates to optimize DC "conditioning" [52] . CD40 and LTβR are quite similar in their mechanisms of signaling, utilizing TRAF adaptors and competent in noncanonical NFκB signaling, although unlike LTβR, CD40 activates TRAF6 pathways.…”

Section: Functions In Host Defense Regulated By Tnfr Superfamilymentioning

confidence: 99%

“…Bone marrow-derived mast cells express LTβR and triggering of LTβR signaling using physiological or pharmacological approaches induced the production of cytokines and pro-inflammatory chemokines [51]. The group of J. Gommerman demonstrated that LTα 1 β 2 expression in antigen-specific T cells was required for optimal DC function [52]. Their result also indicated that DC are dysfunctional without LTα 1 β 2 or CD40 ligand expression on antigen-activated T cells.…”

Section: Functions In Host Defense Regulated By Tnfr Superfamilymentioning

confidence: 99%

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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“…Thus, tumor antigens that are cross-presented by mature DCs are more likely to induce tumor immunity. A recent study has shown that global LTβR signaling is required for maximal expression of CD86 on Ag-bearing DC and for efficient priming of T cells, and that the LTβR signaling on the DCs is essential to condition them for T cell priming [63]. Moreover, the DCs that become non-functional in the absence of CD40L, an important signal for DC maturation, on Ag-specific T cells can be overcome by stimulating LTβR [63].…”

Section: Light Regulates Dcs At the Tumor Site To Promote Primingmentioning

confidence: 99%

“…A recent study has shown that global LTβR signaling is required for maximal expression of CD86 on Ag-bearing DC and for efficient priming of T cells, and that the LTβR signaling on the DCs is essential to condition them for T cell priming [63]. Moreover, the DCs that become non-functional in the absence of CD40L, an important signal for DC maturation, on Ag-specific T cells can be overcome by stimulating LTβR [63]. This observation is consistent with previous findings that LIGHT can cooperate with CD40L to induce the maturation of monocyte-derived DCs [64].…”

Section: Light Regulates Dcs At the Tumor Site To Promote Primingmentioning

confidence: 99%

Targeting tumors with LIGHT to generate metastasis-clearing immunity

Yü¹,

Fu²

2008

Cytokine & Growth Factor Reviews

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Metastastic diseases cause the majority of morbidity and mortality of cancer patients. Established tumors form both physical and immunological barriers to limit immune detection and destruction. Current immunotherapy of vaccination and adoptive transfer shows limited effect at least in part due to the existing barriers in the tumors and depending on the knowledge of tumor antigens. Tumor necrosis factor superfamily member 14 (TNFSF14) LIGHT interacts with stromal cells, dendritic cells, NK cells, naïve and activated T cells and tumor cells inside the tumor tissues via its two functional receptors, HVEM and lymphotoxin β receptor (LTβR). Targeting tumor tissues with LIGHT leads to augmentation of priming, recruitment, and retention of effector cells at tumor sites, directly or indirectly, to induce strong anti-tumor immunity to inhibit the growth of primary tumors as well as eradicate metastases. Intratumor treatment would break tumor barriers and allow strong immunity against various tumors without defining tumor antigens. This review summarizes recent findings to support that LIGHT is a promising candidate for an effective cancer immunotherapy.

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Expression of lymphotoxin-αβ on antigen-specific T cells is required for DC function

Cited by 56 publications

References 37 publications

Lymphotoxin β Receptor Is Required for the Migration and Selection of Autoreactive T Cells in Thymic Medulla

Lymphotoxin β Receptor Is Required for the Migration and Selection of Autoreactive T Cells in Thymic Medulla

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

Targeting tumors with LIGHT to generate metastasis-clearing immunity

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