Immune recognition of phosphoantigen-butyrophilin molecular complexes by γδ T cells

Gamma-delta (γδ) T cells are an important component of the immune system. They are often enriched in non-lymphoid tissues and exhibit diverse functional attributes including rapid activation, cytokine production, proliferation, and acquisition of cytotoxicity following both TCR-dependent and TCR-independent stimulation, but poor capacity for immunological memory. They can detect a broad range of antigens, although typically not peptide-MHC complexes in contrast to alpha-beta (αβ) T cells. In humans, a prominent population of γδ T cells, defined as Vγ9Vδ2⁺ cells, reacts to small phosphorylated non-peptide "phosphoantigens" (pAgs). The molecular mechanism underpinning this recognition is poorly defined, but is known to involve butyrophilin family members and appears to involve indirect pAg recognition via alterations to butyrophilin molecular complexes. In this review, we discuss recent advances in our understanding of pAg recognition by γδ T cells including the role of butyrophilins and in particular, a newly described role for butyrophilin 2A1.