Cutting Edge: B and T Lymphocyte Attenuator and Programmed Death Receptor-1 Inhibitory Receptors Are Required for Termination of Acute Allergic Airway Inflammation

Deppong, Christine; Juehne, Twyla; Hurchla, Michelle A.; Friend, Lindzy D.; Shah, Dulari D.; Rose, Christine M.; Bricker, Traci L.; Shornick, Laurie P.; Crouch, Erika C.; Murphy, Theresa L.; Holtzman, Michael J.; Murphy, Kenneth M.; Green, Jonathan M.

doi:10.4049/jimmunol.176.7.3909

Cited by 79 publications

(79 citation statements)

References 16 publications

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“…This finding is consistent with already published data showing that BTLA is induced upon TCR-mediated stimulation of T cells in vitro (20). Recently, it has been shown in vivo that BTLA contributes to the termination of allergic airway inflammation because BTLA-deficient mice exhibit a prolonged infiltration of lymphocytes and eosinophils in bronchoalveolar lavage fluid (22). During blood-stage PbA infection, we found that BTLA expression on splenic CD4 ؉ as well as CD8 ϩ T cells increased during the course of disease.…”

Section: Discussionsupporting

confidence: 93%

“…In accordance with the role of BTLA as a negative receptor, mice lacking the full-length form of BTLA are hyperresponsive to TCR-mediated activation of T cells (15). In acute allergic airway inflammation, BTLA in combination with PD-1 contributes to the termination of this TH2-mediated immune response, because mice lacking these receptors show prolonged lung inflammation (22). Moreover, it has been demonstrated in an in vivo transplantation model that BTLA is involved in the acceptance of partially MHC-mismatched cardiac allografts (23).…”

mentioning

confidence: 74%

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Ligation of B and T Lymphocyte Attenuator Prevents the Genesis of Experimental Cerebral Malaria

Lepenies

Pfeffer

Hurchla

et al. 2007

The Journal of Immunology

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B and T lymphocyte attenuator (BTLA; CD272) is a coinhibitory receptor that is predominantly expressed on T and B cells and dampens T cell activation. In this study, we analyzed the function of BTLA during infection with Plasmodium berghei ANKA. Infection of C57BL/6 mice with this strain leads to sequestration of leukocytes in brain capillaries that is associated with a pathology resembling cerebral malaria in humans. During the course of infection, we found an induction of BTLA in several organs, which was either due to up-regulation of BTLA expression on T cells in the spleen or due to infiltration of BTLA-expressing T cells into the brain. In the brain, we observed a marked induction of BTLA and its ligand herpesvirus entry mediator during cerebral malaria, which was accompanied by an accumulation of predominantly CD8+ T cells, but also CD4+ T cells. Application of an agonistic anti-BTLA mAb caused a significantly reduced incidence of cerebral malaria compared with control mice. Treatment with this Ab also led to a decreased number of T cells that were sequestered in the brain of P. berghei ANKA-infected mice. Our findings indicate that BTLA-herpesvirus entry mediator interactions are functionally involved in T cell regulation during P. berghei ANKA infection of mice and that BTLA is a potential target for therapeutic interventions in severe malaria.

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 74%

Ligation of B and T Lymphocyte Attenuator Prevents the Genesis of Experimental Cerebral Malaria

Lepenies

Pfeffer

Hurchla

et al. 2007

The Journal of Immunology

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“…BTLA is a coinhibitory receptor with structural similarities to CTLA-4 and PD-1, and the negative cosignaling role of BTLA is supported by observations of attenuated lymphocyte responses after in vitro cross-linking (20). Although BTLA-deficient mice have normal B and T cell development, these mice have exacerbated responses in the experimental autoimmune encephalomyelitis model (16) and worse disease in a model of allergic airway inflammation (21). BTLA targeting has been implicated in the accelerated rejection of partially mismatched cardiac grafts but also in prolongation of fully-mismatched allografts (22), and we hypothesize that BTLA negative cosignaling may be important in the context of costimulatory blockade in islet allograft survival.…”

Section: Introductionmentioning

confidence: 97%

Combined Coinhibitory and Costimulatory Modulation with Anti-BTLA and CTLA4Ig Facilitates Tolerance in Murine Islet Allografts

Truong

Plester

Hancock

et al. 2007

American Journal of Transplantation

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Complex interactions between positive and negative cosignaling receptors ultimately determine the fate of the immune response. The recently identified coinhibitory receptor, B and T lymphocyte attenuator (BTLA), contributes to regulation of autoimmune and potentially alloimmune responses. We investigated the role of BTLA in a fully major histocompatibility complex-mismatched mouse islet transplant model. We report that anti-BTLA mAb (6F7) alone does not accelerate graft rejection. Rather, while CTLA4Ig alone improved allograft survival, the addition of anti-BTLA mAb to CTLA4Ig led to indefinite (>100 days) allograft survival. Immediately after treatment with anti-BTLA mAb and CTLA4Ig, islet allografts showed intact islets and insulin production despite a host cellular response, with local accumulation of Foxp3+ cells. We clearly demonstrate that combined therapy with anti-BTLA mAb and CTLA4Ig mice induced donor-specific tolerance, since mice accepted a second donor-specific islet graft without further treatment and rejected third party grafts. CTLA4Ig and anti-BTLA mAb limited the initial in vivo proliferation of CFSE-labeled allogeneic lymphocytes, and anti-BTLA mAb enhanced the proportion of PD-1 expressing T cells while depleting pathogenic BTLA+ lymphocytes. We conclude that targeting the BTLA pathway in conjunction with CTLA4Ig costimulatory blockade may be a useful strategy for promoting immunological tolerance in murine islet allografts.

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“…Initially, we have shown that the sensitivity to experimental autoimmune encephalomyelitis as well as T cell-dependent Ab responses is increased in BTLA 2/2 mice (3). It has also been reported that BTLA 2/2 mice exhibit a rapid rejection of partially MHC-mismatched cardiac allograft (9), persistent allergic airway inflammation following Ag challenge (10,11), and an acceleration of experimental colitis (12). These findings indicate that BTLA is crucial for dampening immune responses mediated by T cells.…”

mentioning

confidence: 84%

Protective Roles of B and T Lymphocyte Attenuator in NKT Cell-Mediated Experimental Hepatitis

Iwata¹,

Watanabe²,

Oya³

et al. 2009

The Journal of Immunology

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Although B and T lymphocyte attenuator (BTLA) was originally identified as an inhibitory coreceptor selectively expressed on Th1 cells and B cells, recent studies have revealed that BTLA is expressed on a variety of cells, including macrophages, dendritic cells, and NK cells, and modulates their functions. However, the role of BTLA in the regulation of NKT cell function remains unknown. In this study, we found that BTLA was expressed on NKT cells at the levels similar to those on T cells and that BTLA-deficient (BTLA−/−) NKT cells produced larger amounts of IL-4 and IFN-γ upon α-glactosylceramide stimulation as compared with wild-type (WT) NKT cells. In vivo, BTLA−/− mice produced larger amounts of IL-4 and IFN-γ upon Con A injection and were more susceptible to Con A-induced hepatitis than WT mice. In addition, the augmentation of Con A-induced hepatitis in BTLA−/− mice was not observed in BTLA/NKT-double deficient mice. Moreover, NKT−/− mice reconstituted with BTLA−/− NKT cells were significantly more susceptible to Con A-induced hepatitis as compared with NKT −/− mice reconstituted with WT NKT cells. These results suggest that BTLA functions as the inhibitory coreceptor of NKT cells and plays a critical role in the prevention of NKT cell-mediated liver injury.

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Cutting Edge: B and T Lymphocyte Attenuator and Programmed Death Receptor-1 Inhibitory Receptors Are Required for Termination of Acute Allergic Airway Inflammation

Cited by 79 publications

References 16 publications

Ligation of B and T Lymphocyte Attenuator Prevents the Genesis of Experimental Cerebral Malaria

Ligation of B and T Lymphocyte Attenuator Prevents the Genesis of Experimental Cerebral Malaria

Combined Coinhibitory and Costimulatory Modulation with Anti-BTLA and CTLA4Ig Facilitates Tolerance in Murine Islet Allografts

Protective Roles of B and T Lymphocyte Attenuator in NKT Cell-Mediated Experimental Hepatitis

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