Butyrophilin-like 3 Directly Binds a Human Vγ4+ T Cell Receptor Using a Modality Distinct from Clonally-Restricted Antigen 2019 Wilcox et al

[Andy]

Highlights​

• BTNL3 binds directly and specifically to Vγ4+ TCRs via its IgV domain
• The superantigen-like binding mode focuses on germline-encoded TCR regions
• In contrast, γδ TCR binding to a clonally restricted antigen is CDR3-mediated
• Mutagenesis indicates parallels with BTN3A1-mediated activation of Vγ9Vδ2 T cells

Summary​

Butyrophilin (BTN) and butyrophilin-like (BTNL/Btnl) heteromers are major regulators of human and mouse γδ T cell subsets, but considerable contention surrounds whether they represent direct γδ T cell receptor (TCR) ligands. We demonstrate that the BTNL3 IgV domain binds directly and specifically to a human Vγ4+ TCR, “LES” with an affinity (∼15–25 μM) comparable to many αβ TCR-peptide major histocompatibility complex interactions. Mutations in germline-encoded Vγ4 CDR2 and HV4 loops, but not in somatically recombined CDR3 loops, drastically diminished binding and T cell responsiveness to BTNL3-BTNL8-expressing cells. Conversely, CDR3γ and CDR3δ loops mediated LES TCR binding to endothelial protein C receptor, a clonally restricted autoantigen, with minimal CDR1, CDR2, or HV4 contributions. Thus, the γδ TCR can employ two discrete binding modalities: a non-clonotypic, superantigen-like interaction mediating subset-specific regulation by BTNL/BTN molecules and CDR3-dependent, antibody-like interactions mediating adaptive γδ T cell biology. How these findings might broadly apply to γδ T cell regulation is also examined.

Open access

 

[SNT Gatchaman]

See also Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children MIS-C (2024)

 

[Hutan]

There's an editorial - often these are a bit more accessible and context-setting than the paper
Docking Complete: A Step Further toward the Holy Grail of γδ T Cell Biology

Gamma delta T cells (γδ T cells) are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ (alpha beta) T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells. Their highest abundance is in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

 

[Hutan]

BiomapAI artificial intelligence multiomics framework modelling of myalgic encephalomyelitis chronic fatigue syndrome, 2024, Xiong et al
mentions gdT cells

Thus, we proposed several innovative mechanistic hypotheses for MECFS: Disrupted microbial functions - SCFA (butyrate), BCAA (amino acid), tryptophan, benzoate - lost connection with plasma lipids and bile acids, and activated inflammatory and mucosal immune cells (MAIT, gdT cells) with INFgamma; and GzA secretion. These abnormal dynamics are linked to key disease symptoms, including gastrointestinal issues, fatigue, and sleep problems.