TL1A: A key inflammatory cytokine in chronic intestinal inflammation and fibrosis-related diseases

• Gene Information: TNF superfamily member 15 (TNFSF15, also known as TL1A) is a protein-coding gene located on chromosome 9q32. This cytokine is a ligand for the receptors TNFRSF25 (also known as DR3) and TNFRSF6B (also known as DcR3).
• Protein Expression: TL1A is expressed in various immune cells (such as monocytes, macrophages, dendritic cells, and T cells) as well as in non-immune cells (such as synovial fibroblasts and endothelial cells). TL1A is a type II transmembrane protein that exists in either membrane-bound (mTL1A) or soluble (sTL1A) forms.
• Signaling Pathway: TL1A binds to death receptor 3 (DR3), providing costimulatory signals for downstream signaling pathways, thereby regulating the proliferation, activation, and apoptosis of effector cells, and the production of cytokines and chemokines.
• Therapeutic Inhibition: Blocking the interaction between TL1A and DR3 can reduce the severity of autoimmune and inflammatory diseases, as demonstrated in preclinical inflammatory bowel disease (IBD) models.

PD-1: An immune checkpoint receptor and therapeutic target for restoring T-cell anti-tumor activity

• Gene Information: PD-1 (PDCD1/CD279) is an inhibitory immune checkpoint receptor expressed mainly on activated T cells. PD-L1 (CD274/B7-H1) is a major PD-1 ligand expressed by antigen-presenting cells and many tumor cells.
•  Protein Expression: PD-1 is induced after antigen-specific T-cell stimulation and can be sustained during chronic activation or T-cell exhaustion. PD-L1 expression may be constitutive in tumor cells or induced by inflammatory cytokines such as IFN-γ.
• Signaling Pathway: PD-1/PD-L1 engagement suppresses TCR/CD28 downstream signaling, reducing T-cell activation, cytokine production, cytotoxicity, and tumor-cell killing.
• Therapeutic Inhibition: Anti-human PD-1 antibodies block PD-1-mediated inhibitory signaling and restore cytotoxic T-cell activity. B-hPD-1 plus mice provide an immune-competent in vivo platform for evaluating anti-human PD-1 antibodies and combination therapies.

TL1A: A key inflammatory cytokine in chronic intestinal inflammation and fibrosis-related diseases

• Gene Information: TNF superfamily member 15 (TNFSF15, also known as TL1A) is a protein-coding gene located on chromosome 9q32. This cytokine is a ligand for the receptors TNFRSF25 (also known as DR3) and TNFRSF6B (also known as DcR3).
•  Protein Expression: TL1A is expressed in various immune cells (such as monocytes, macrophages, dendritic cells, and T cells) as well as in non-immune cells (such as synovial fibroblasts and endothelial cells). TL1A is a type II transmembrane protein that exists in either membrane-bound (mTL1A) or soluble (sTL1A) forms.
• Signaling Pathway: TL1A binds to death receptor 3 (DR3), providing costimulatory signals for downstream signaling pathways, thereby regulating the proliferation, activation, and apoptosis of effector cells, and the production of cytokines and chemokines.
•  Therapeutic Inhibition: Blocking the interaction between TL1A and DR3 can reduce the severity of autoimmune and inflammatory diseases, as demonstrated in preclinical inflammatory bowel disease (IBD) models.

Soluble TL1A expression analysis in wild-type C57BL/6 mice and homozygous B-hTL1A/hPD-1 plus mice by ELISA. Bone marrow-derived dendritic cells (BMDCs) were produced by culturing bone marrow from wild-type C57BL/6 mice (+/+) and homozygous B-hTL1A/hPD-1 plus mice (H/H;H/H) and stimulated with LPS in vitro. After stimulation, cell culture supernatants were collected, and the levels of soluble TL1A were measured using a species-specific human TL1A ELISA kit. Soluble human TL1A was exclusively detectable in homozygous B-hTL1A/hPD-1 plus mice but not in wild-type C57BL/6 mice. Values are expressed as mean ± SEM. ND: not detectable.

Strain specific PD-1 expression analysis in wild-type C57BL/6 mice and homozygous B-hTL1A/hPD-1 plus mice by flow cytometry. Splenocytes were collected from wildtype C57BL/6 mice (+/+) and homozygous B hTL1A/hPD 1 plus mice (H/H;H/H), stimulated with anti CD3ε in vivo for 24 hours. The protein expression was analyzed with antimouse PD 1 antibody (Biolegend, 109104) and anti human PD 1 antibody (Biolegend, 329908) by flow cytometry. Mouse PD 1 was only detectable in wild type C57BL/6 mice.Human PD 1 was only detectable in homozygous B hTL1A/hPD 1 plus mice.