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BTLA

Official Full Name
Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey) b- and T-lymphocyte attenuator-like DNA.
Background
This gene encodes a member of the immunoglobulin superfamily. The encoded protein contains a single immunoglobulin (Ig) domain and is a receptor that relays inhibitory signals to suppress the immune response. Alternative splicing results in multiple transcript variants. Polymorphisms in this gene have been associated with an increased risk of rheumatoid arthritis.
Synonyms
BTLA; B and T lymphocyte associated; B- and T-lymphocyte attenuator; BTLA1; CD272; B and T lymphocyte attenuator; B- and T-lymphocyte-associated protein; FLJ16065; MGC129743

Recent Research Progress

B and T lymphocyte attenuator (BTLA) has been identified as a novel co-suppressor receptor, expressed by most lymphocytes, and exhibit structural and functional similarities to Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1). Because tumor-infiltrating immune cells express multiple co-repressor receptors, it is hypothesized that dual or triple blocking of co-suppressor receptors will enhance anti-tumor immunity. Indeed, combined blockade of the PD-1⁄programmed death-ligand 1 (PD-L1) and CTLA-4 pathways, and that of the PD-1⁄PD-L1 and lymphocyte activation gene 3 (LAG3) pathways, has been exhibited to enhance antitumor effects in a human clinical study and animal model studies. In addition, BTLA inhibits lymphocyte activation when interacting with herpesvirus entry mediator (HVEM). The BTLA/HVEM pathway appears to be a novel immune escape method that is considered a key factor in the physiological processes of inflammation and tumorigenesis. Therefore, BTLA is expected to be a potential therapeutic target for many disease states.

BTLA and HCC

PD-1 on tumor infiltrating T cells has become a recognized marker in cancer called T cell "failure" status. Recently, studies have shown that both PD-1 and BTLA were significantly up-regulated on CD4+ T cells from tumor compared with those from paired non-tumor liver in hepatocellular carcinoma (HCC) patients. Interestingly, more than 85% of BTLA+ CD4+ T cells are PD-1 expressing cells and represented about 50% of PD-1+ CD4+ T cells in tumors, and that level of BTLA+ PD-1+ tumor CD4+ T cells are selectively associated with advanced stage HCC. BTLA+ identified a highly dysfunctional PD-1-expressing CD4+ T cell subset, whereas BTLA-defined PD-1+ CD4+ T cells undergo activation in HCC. Importantly, blocking PD-L1 restored the ability of IFNg/TNF-α production in BTLA+ PD-1+ tumor CD4+ T cells, but partially inhibited the activation of BTLAPD-1+ CD4+ T cells. In addition, the results suggest that BTLA signaling is also involved in the suppressing CD4+ T cell function in HCC. In conclusion, BTLA can identify the unique function of PD-1 expressing CD4+ T cells in human cancers, which not only promotes understanding of inhibitory receptor blockade, but also provides new targets for clinical prediction of the response to these immunotherapies.

BTLA and GC

Worldwide, gastric cancer (GC) remains one of the most pathogenic and fatal malignancies. Recent studies have demonstrated the relevance of BTLA, HVEM and gastric cancer. The expression of BTLA and HVEM is increased in most gastric cancers, which is associated with progression and poor prognosis. BTLA and HVEM may be new prognostic indicators, and the BTLA / HVEM pathway is considered a promising anti-cancer treatment target.

BTLA and GBC

Recently, Seiji Oguro et al. investigated 211 cases of Gallbladder cancer (GBC), 21 cases of chronic cholecystitis (CC), and 11 cases of xanthogranulomatous cholecystitis (XGC) using immunohistochemistry to detect tissue-infiltrating immune cells and their expression of BTLA and Cbl-b, and carried out correlation and survival analyses. The density of invasive T cells in CC and XGC was significantly higher than that of GBC. The density ratio of BTLAcells to CD8+ T cells (BTLA/CD8) and the density ratio of Cbl-b+ cells to CD8+ T cells (Cbl-b/CD8) were significantly higher in GBC than in CC and XGC. The FOXP3/CD4, BTLA/CD8 and Cbl-b/CD8 ratios were significantly correlated with each other and were also significantly associated with malignant phenotypes. Survival analysis showed that lower-density tumor-infiltrating CD8+ cells, higher Foxp3/CD4, BTLA/CD8 and Cbl-b/CD8 ratios were significantly associated with shorter overall survival and disease-free survival in GBC patients. Multivariate analysis showed that factor M, perineural invasion, BTLA/CD8 and Cbl-b/CD8 were closely correlated with shorter overall survival. These findings indicate that a higher proportion of BTLA / CD8 and Cbl-b / CD8 are independent indicators of adverse outcomes in GBC patients, and up-regulation of BTLA in cancerous tissues is involved in the inhibition of anti-tumor immunity.

BTLA and Sepsis

Sepsis is a deadly inflammation that usually leads to an immunosuppressive state; however, events leading to this state are still poorly understood. Recently, some studies have shown that the percentage of peripheral blood BTLA+ CD4+ lymphocytes is significantly higher in patients with septic ICU compared with critically ill non-septic individuals, and an increased BTLA+ CD4+ lymphocyte frequency in critically ill non-septic patients was associated with a subsequent infection. Therefore, BTLA can be used as a biomarker to help determine the development of nosocomial infections. Additionally, BTLA expression contributes to primary and secondary lymphoid apoptotic cell loss in experimental sepsis mice; thus, BTLA-induced apoptosis of lymphocytes may be a mechanism for increased risk of nosocomial infection in critically ill patients.

Taken together, the above data strongly suggest that BTLA can effectively inhibit CD4+ T cell and B cell function and reduce pro-survival signals in CD4+ T cells, which play an important role in the pathogenesis of autoimmune, tumor and inflammatory diseases. Therefore, further understanding of the functional role of BTLA may help develop new disease diagnosis or immunotherapy strategies.

References:

  1. Qiyi Zhao, et al. BTLA identifies dysfunctional PD-1-expressing CD4+ T cells in human hepatocellular carcinoma. OncoImmunology, 2016, 5:12
  2. Edward R Sherwood, et al. BTLA as a biomarker and mediator of sepsisinduced immunosuppression. Critical Care, 2013, 17:1022
  3. Shubin, et al. B and T lymphocyte attenuator expression on CD4+ T-cells associates with sepsis and subsequent infections in ICU patients. Critical Care, 2013, 17:R276
  4. Anna Lange, et al. Soluble B and T Lymphocyte Attenuator Correlates to Disease Severity in Sepsis and High Levels Are Associated with an Increased Risk of Mortality. PLoS ONE, 2016, 12(1): e0169176
  5. Xiuwen Lan, et al. Increased BTLA and HVEM in gastric cancer are associated with progression and poor prognosis. OncoTargets and Therapy, 2017, 10: 919–926
  6. Seiji Oguro, et al. Clinical significance of tumor-infiltrating immune cells focusing on BTLA and Cbl-b in patients with gallbladder cancer. Cancer Science, 2015, 106, 1750–1760

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