BTLA suppress acute rejection via regulating TCR downstream signals and cytokines production in kidney transplantation and prolonged allografts survival

Zhang, Jiayi; Zhang, Hengcheng; Wang, Zijie; Yang, Haiwei; Chen, Hao; Cheng, Hong; Zhou, Jiajun; Zheng, Ming; Tan, Ruoyun; Gu, Min

doi:10.1038/s41598-019-48520-7

Cited by 19 publications

(22 citation statements)

References 42 publications

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“…First, the number of samples being screened for cox regression analysis is too small, only transcriptomics expression of BTLA with full clinical data was analyzed in this study. Second, cytokines not only carry information between tumors and immune cells but also be secreted by immune cells, playing an important role in TME ( Burkholder et al, 2014 ; Zhang J. et al, 2019 ). Cytokines-cytokines receptor interaction pathway is the top terms in KEGG analysis, but the role of BTLA in this pathway needs further validation.…”

Section: Discussionmentioning

confidence: 99%

Friend or Foe: Prognostic and Immunotherapy Roles of BTLA in Colorectal Cancer

Song

2020

Front. Mol. Biosci.

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Background: B and T lymphocyte attenuator (BTLA) is a co-signaling protein belonging to the CD28 immunoglobulin superfamily. However, the role of BTLA in prognosis and immunotherapy of colorectal cancer (CRC) remains unclear. Methods: We evaluated the expression of BTLA via the Oncomine and the cancer genome atlas (TCGA) database. We research the outcome among different BTLA expression patients by Kaplan-Meier curve. We used the Chi-Squared test and Cox regression analysis to identify potential risk factors. Besides, the correlations between BTLA and cancer immune infiltration were investigated via CIBERSORT. Results: Various cohorts showed that BTLA expression was lower in CRC compared to corresponding normal tissue. Moreover, low BTLA expression was correlated with poor overall survival in TCGA cohorts and Gene Expression Omnibus cohorts (GSE29623 and GSE17536). Low BTLA expression was associated with less lymph node metastasis (p = 0.0123). In the Cox proportional hazards model, BTLA was identified as a favorable prognostic factor. Naive B cells, memory B cells, CD8 T cells, CD4 memory resting T cells, follicular helper T (Tfh) cells, monocytes, resting natural killing (NK) cells, M0 macrophages, M1 macrophages, resting mast cells, and activated mast cells were affected by BTLA expression (all p < 0.01). Correlated immune markers and functional enrichment analysis revealed BTLA functioned in the T cell receptor signaling pathway, B cell receptor signaling pathway, and NK cell-mediated cytotoxicity pathway. Conclusion: These analyses suggest BTLA is a potential factor for extended survival and closely related to CD8 T cells, Tfh cells, B cells, and NK cells in CRC. We summarize these results that BTLA can be used as a prognostic biomarker and might contribute to developing novel CRC immunological treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Friend or Foe: Prognostic and Immunotherapy Roles of BTLA in Colorectal Cancer

Song

2020

Front. Mol. Biosci.

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“…Rat kidney transplantations were carried out according to a previously described procedure ( 26 ). Two experienced microsurgeons performed the surgeries in a sterile environment.…”

Section: Methodsmentioning

confidence: 99%

“…The inhibitory effect of BTLA on the immune response has been confirmed by recent studies; for instance, targeted BTLA therapy can inhibit rejection in a mouse heart transplantation model ( 24 ) but less so in kidney transplantation. Our previous research has shown that the BTLA pathways were involved in the pathogenesis of AR in biopsy-proven recipients following kidney transplantation, and BTLA overexpression can suppress TCMR by regulating T cell receptor downstream signals ( 25 , 26 ). Additionally, several studies indicated the potential value of combining costimulatory or costimulatory molecules in disease treatment, which may reduce adverse effects through a lower single dose and provides new ideas for the prevention of kidney transplant rejection ( 27 ).…”

Section: Introductionmentioning

confidence: 99%

Combined Immunotherapy With Belatacept and BTLA Overexpression Attenuates Acute Rejection Following Kidney Transplantation

et al. 2021

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BackgroundCostimulatory blockade provides new therapeutic opportunities for ensuring the long-term survival of kidney grafts. The adoption of the novel immunosuppressant Belatacept has been limited, partly due to concerns regarding higher rates and grades of acute rejection in clinical trials. In this study, we hypothesized that a combined therapy, Belatacept combined with BTLA overexpression, may effectively attenuate acute rejection after kidney transplantation.Materials and MethodsThe rat kidney transplantation model was used to investigate graft rejection in single and combined therapy. Graft function was analyzed by detecting serum creatinine. Pathological staining was used to observe histological changes in grafts. The expression of T cells was observed by immunohistochemistry and flow cytometry. In vitro, we constructed an antigen-stimulated immune response by mixed lymphocyte culture, treated with or without Belatacept and BTLA-overexpression adenovirus, to observe the proliferation of receptor cells and the expression of cytokines. In addition, western blot and qRT-PCR analyses were performed to evaluate the expression of CTLA-4 and BTLA at various time points during the immune response.ResultsIn rat models, combined therapy reduced the serum creatinine levels and prolonged graft survival compared to single therapy and control groups. Mixed acute rejection was shown in the allogeneic group and inhibited by combination treatment. Belatacept reduced the production of DSA and the deposition of C4d in grafts. Belatacept combined with BTLA overexpression downregulated the secretion of IL-2 and IFN-γ, as well as increasing IL-4 and IL-10 expression. We also found that Belatacept combined with BTLA overexpression inhibited the proliferation of spleen lymphocytes. The duration of the elevated expression levels of CTLA-4 and BTLA differentially affected the immune response.ConclusionBelatacept combined with BTLA overexpression attenuated acute rejection after kidney transplantation and prolonged kidney graft survival, which suggests a new approach for the optimization of early immunosuppression after kidney transplantation.

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“…Vital factors in T-cell signaling pathways, including mitogen-associated protein kinases (MAPKs), nuclear factor-kappa B (NF-κB), and nuclear factor of activated T cells (NFAT), are also significantly repressed by overexpression of BTLA. 39 The transcriptomic profile of ADAM12 −/− T cells strongly establishes that ADAM12 is a costimulatory molecule that cooperates with TCR signaling to trigger successful T-cell activation, proliferation, and Th1 cell fate and maintenance. ADAM12 −/− T cells are defective in inducing skin inflammation Next, we determined whether the transcriptomic profile of antigen-driven ADAM12 −/− T cells is associated with their capacity to establish inflammation and is stable in vivo, using the delayedtype hypersensitivity (DTH) T-cell-mediated inflammatory model.…”

Section: Transcriptomic Profiling Of Adam12 −/− T Cells Reveals Dysrementioning

confidence: 99%

ADAM12 is a costimulatory molecule that determines Th1 cell fate and mediates tissue inflammation

et al. 2020

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A disintegrin and metalloproteinase (ADAM)12 was previously found to be expressed in T cells in the inflamed brain. However, the function of ADAM12 in T-cell responses in general and in tissue inflammation has not been examined. Here, we studied the role of ADAM12 in T-cell responses, fate determination on activation, and its functions in T cells to mediate tissue inflammation. We identified ADAM12 as a costimulatory molecule that is expressed on naive T cells and downregulated on stimulation. ADAM12 mimics CD28 costimulatory signaling to activate and induce the proliferation of T-helper 1 (Th1) cells. Monoclonal ADAM12 Fab antibodies trigger T-cell activation by amplifying TCR signaling to stimulate T-bet-mediated IFNγ production. Lack of genomic ADAM12 and its knockdown in T cells diminished T-bet and IFNγ production in Th1 cells, whereas other T cells, including Th17 cells, were unaffected. ADAM12 had similar functions in vivo on myelin antigen (MOG 35-55)-induced T-cell activation. We found that genetic loss of ADAM12 profoundly alleviated Th1-mediated neuroinflammation and thus disease severity in experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Transcriptomic profiling of MOG 35-55-specific ADAM12 −/− T cells revealed differentially expressed genes that are important for T-cell activation, proliferation, and costimulatory signaling and Th1 pathogenicity, consistent with their inability to cause T-cell-mediated skin inflammation in a model of adoptive delayed-type hypersensitivity. We conclude that ADAM12 is a T-cell costimulatory molecule that contributes to the pathogenesis of tissue inflammation and a potential target for the treatment of Th1-mediated diseases.

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BTLA suppress acute rejection via regulating TCR downstream signals and cytokines production in kidney transplantation and prolonged allografts survival

Cited by 19 publications

References 42 publications

Friend or Foe: Prognostic and Immunotherapy Roles of BTLA in Colorectal Cancer

Friend or Foe: Prognostic and Immunotherapy Roles of BTLA in Colorectal Cancer

Combined Immunotherapy With Belatacept and BTLA Overexpression Attenuates Acute Rejection Following Kidney Transplantation

ADAM12 is a costimulatory molecule that determines Th1 cell fate and mediates tissue inflammation

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