Butyrophilins (BTN) belong to the Ig superfamily and typically consist of extracellular Ig-like domains (IgV and IgC), a transmembrane domain, and for some an intracellular B30.2 signaling domain. They share structural homology with B7 family members. Thirteen members of the BTN family have been described: BTN1A1, BTN2A1, BTN2A2, BTN2A3, BTN3A1, BTN3A2, BTN3A3, Butyrophilin-like protein 2 (BTNL2), BTNL3, BTNL8, BTNL9, BTNL10, and SKINT-like (SKINTL).1
Other than BTN2A1 that binds DC-SIGN (CD209) on dendritic cells and monocytes, the receptors are largely unknown.2 BTN/BTNL proteins are widely expressed on immune cells and epithelial cells, and several studies suggest they have immunoregulatory roles. For example, BTN1A1 and BTN2A2 inhibit early signaling events in activated T cells and prevent cell cycle entry, while BTNL2 suppresses T cell activation and promotes Treg development.3, 4, 5 BTNL8 co-stimulates proliferation and cytokine production of activated CD4+ and CD8+ T cells.6 Furthermore, BTN3A1 negatively regulates T cell activation and its intracellular B30.2 domain may play a role in pAg detection.7 BTN and BTNL proteins are expressed in the intestine and regulate tissue integrity, local immune responses, and inflammation. BTNL1 and BTNL6 form heteromeric complexes that enhance the proliferative activity of intraepithelial lymphocytes, specifically of a subset of gamma delta T cells. BTNL3 and BTNL8 are expressed on human gut epithelial cells and regulate tissue-specific gamma delta T cells expressing a V gamma 4 TCR.8
The biological functions of BTN/BTNL family members, BTN3A2, BTNL3, and BTNL9 remain largely unknown. Utilizing recombinant ecto-domains, we have examined T cells for the presence of receptors and assessed their functional roles as ligands for T cells. BTN1A1 and BTN3A1, known to suppress T cells, appear to have receptors upregulated upon T cell activation. Treatment of T cells with BTN3A2 and BTNL8 significantly increases anti-CD3 induced IL-2 production, suggesting that both BTN3A2 and BTNL8 act as co-stimulatory ligands. In contrast, BTNL3 and BTNL9 inhibit anti-CD3-induced IL-2 production and T cell proliferation, suggesting that BTNL3 and BTNL9 may act as co-inhibitory ligands.
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