Cutting Edge: B and T Lymphocyte Attenuator Signaling on NKT Cells Inhibits Cytokine Release and Tissue Injury in Early Immune Responses

Miller, Mendy; Sun, Yonglian; Fu, Yang–Xin

doi:10.4049/jimmunol.0900690

Cited by 46 publications

(45 citation statements)

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“…Moreover, an inhibitory function of BTLA has been demonstrated in in vivo transplantation models using MHCmismatched cardiac allografts (12). BTLA-KO mice are also more susceptible to experimental autoimmune encephalomyelitis (1) and Con A-induced hepatitis (13). Triggering BTLA or deleting BTLA highly positive T cells also might have therapeutic significance.…”

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confidence: 99%

B and T Lymphocyte Attenuator Restricts the Protective Immune Response against Experimental Malaria

Adler

Steeg

Pfeffer

et al. 2011

The Journal of Immunology

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The immune response against the blood stage of malaria has to be tightly regulated to allow for vigorous antiplasmodial activity while restraining potentially lethal immunopathologic damage to the host like cerebral malaria. Coinhibitory cell surface receptors are important modulators of immune activation. B and T lymphocyte attenuator (BTLA) (CD272) is a coinhibitory receptor expressed by most leukocytes, with the highest expression levels on T and B cells, and is involved in the maintenance of peripheral tolerance by dampening the activation of lymphocytes. The function of BTLA is described in several models of inflammatory disorders and autoimmunity, but its function in infectious diseases is less well characterized. Also, little is known about the influence of BTLA on non-T cells. In this study, we analyzed the function of BTLA during blood-stage malaria infection with the nonlethal Plasmodium yoelii strain 17NL. We show that BTLA knockout mice exhibit strongly reduced parasitemia and clear the infection earlier compared with wild-type mice. This increased resistance was seen before the onset of adaptive immune mechanisms and even in the absence of T and B cells but was more pronounced at later time points when activation of T and B cells was observed. We demonstrate that BTLA regulates production of proinflammatory cytokines in a T cell-intrinsic way and B cell intrinsically regulates the production of P. yoelii 17NL-specific Abs. These results indicate that the coinhibitory receptor BTLA plays a critical role during experimental malaria and attenuates the innate as well as the subsequent adaptive immune response.

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confidence: 99%

B and T Lymphocyte Attenuator Restricts the Protective Immune Response against Experimental Malaria

Adler

Steeg

Pfeffer

et al. 2011

The Journal of Immunology

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“…In this manner, IL-10 could minimize T lymphocyte proliferation in hepatic sinusoids and prevent hepatocellular injury, with restoration of normal transaminase levels. In addition, IL-10 negatively modulates B lymphocyte proliferation (Gove et al 2009;Miller et al 2009) and consequently reduces total immunoglobulin levels. This hypothesis is supported by an increase in IL-10 synthesis in prophylactically treated AIH mice, followed by greater and faster liver restoration in these mice than in therapeutically treated AIH mice.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulation of liver injury by Ascaris suum extract in an experimental model of autoimmune hepatitis

et al. 2014

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Adult worm extract from Ascaris suum (Asc) has immunosuppressive activity and elicits Th2/IL-4/IL-10 response. This study evaluated the prophylactic and therapeutic effect of Asc in a murine model of concanavalin A (ConA)-induced autoimmune hepatitis (AIH). BALB/c mice received ConA, iv, (20 mg/kg), and three groups of animals were formed: (1) AIH, received only ConA; (2) AIH + Asc prophylactic, treated with Asc (1 mg/ml), ip, 30 min before of the AIH; and (3) AIH + Asc therapeutic, treated with Asc 2 h after the AIH. Plasma transaminase and immunoglobulins (measured at 8 and 24 h and 7 days after treatment) and cytokine production (IL-4, IL-10, IL-13, and IFN-γ) by splenocytes upon ConA and Asc stimulus were compared. The livers were weighed and examined histologically. In the AIH group, there was an increase in liver weight, transaminase levels, and total immunoglobulins. These parameters were reduced by 8-24 h and 7 days in the prophylactic group, but in the therapeutic group, only on day 7. The survival rate of mice in the AIH group was 38.5%, compared to 67% in the therapeutic Asc group. The survival rate of the animals with AIH that were prophylactically treated with Asc was 100%. A decrease of cellular infiltration and high levels of IL-4, IL-10, and IL-13 were induced by Asc. An increase of liver fibrosis was also observed, but with less intensity with prophylactic treatment. Thus, the Ascaris components have an inhibitory effect on AIH, with an intense Th2 immune response.

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“…5,8,9 This signaling characteristic is consistent with its immune inhibitory functions, as BTLA gene-deficient mice exhibit an enhanced susceptibility to autoimmune diseases and increased inflammatory responses. 5,[10][11][12][13][14] BTLA coinhibitory signal is induced by interaction with its endogenous ligand herpesvirus entry mediator (HVEM), a member of tumor necrosis factor-receptor superfamily. 8,15 In addition to BTLA, HVEM has 3 other binding partners, LIGHT (lymphotoxin-like, inducible expression, competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes), CD160 and lymphotoxin-␣.…”

Section: Introductionmentioning

confidence: 99%

Dichotomous regulation of GVHD through bidirectional functions of the BTLA-HVEM pathway

Sakoda

Park

Zhao

et al. 2011

Blood

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B and T lymphocyte attenuator (BTLA) is a coinhibitory receptor that interacts with herpesvirus entry mediator (HVEM), and this interaction regulates pathogenesis in various immunologic diseases. In graftversus-host disease (GVHD), IntroductionActivation of T lymphocytes is regulated by 2 distinct signals: one is a primary signal delivered by T-cell receptor interaction with antigenic peptide/major histocompatibility complex (MHC), and the other is a cosignal delivered by interactions between cosignal receptors on T cells and their ligands on antigen-presenting cells. 1,2 Cosignaling receptors transmit stimulatory or inhibitory signals according to characteristics of their intracellular signaling motifs, and a balance of cosignals defines the fate of T-cell responses (ie, optimal activation or deactivation/tolerance induction). 3,4 Approaches to regulate cosignaling functions have been applied as novel and promising immunotherapies in various disorders, including cancer, infectious diseases, autoimmunity, organ transplantation, and graft-versus-host disease (GVHD).B and T lymphocyte attenuator (BTLA) is a cosignaling molecule that structurally belongs to the immunoglobulin (Ig) superfamily, expressed on broad ranges of immune cells, including T cells, B cells, and dendritic cells (DCs). [5][6][7] Intracellular domain of BTLA has 2 immunoreceptor tyrosine-based inhibition motifs, to which SH2 domain-containing protein tyrosine phosphatase-1 and tyrosine phosphatase-2 are recruited. 5,8,9 This signaling characteristic is consistent with its immune inhibitory functions, as BTLA gene-deficient mice exhibit an enhanced susceptibility to autoimmune diseases and increased inflammatory responses. 5,10-14 BTLA coinhibitory signal is induced by interaction with its endogenous ligand herpesvirus entry mediator (HVEM), a member of tumor necrosis factor-receptor superfamily. 8,15 In addition to BTLA, HVEM has 3 other binding partners, LIGHT (lymphotoxin-like, inducible expression, competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes), CD160 and lymphotoxin-␣. 16 LIGHT-HVEM interaction transmits HVEM-positive cosignal into T cells via activation of nuclear factor-B (NF-B) signaling pathway. [16][17][18] HVEM interactions with BTLA and LIGHT are dependent on distinct extracellular regions of HVEM (ie, cysteine-rich domain-1 for BTLA while opposing cysteine-rich domain-2 and -3 sites for LIGHT binding), and it has been suggested that ternary LIGHT-HVEM-BTLA complex either augments or disrupts HVEM-BTLA interactions according to soluble or membrane form of LIGHT. 19 In contrast to negative cosignaling functions of BTLA, recent studies also suggested prosurvival effects of BTLA. For instance, in nonirradiated parent-into-F1 GVHD model, transfer of BTLAknockout (KO) donor T cells resulted in significantly diminished donor-antihost responses because of an impaired donor T-cell survival. 20 In addition, intestinal inflammation induced by a transfer of BTLA-KO T cells into Rag-KO mice was ...

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Cutting Edge: B and T Lymphocyte Attenuator Signaling on NKT Cells Inhibits Cytokine Release and Tissue Injury in Early Immune Responses

Cited by 46 publications

References 24 publications

B and T Lymphocyte Attenuator Restricts the Protective Immune Response against Experimental Malaria

B and T Lymphocyte Attenuator Restricts the Protective Immune Response against Experimental Malaria

Immunomodulation of liver injury by Ascaris suum extract in an experimental model of autoimmune hepatitis

Dichotomous regulation of GVHD through bidirectional functions of the BTLA-HVEM pathway

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