WC1-mediated co-stimulation in γδ T cells: Insights from ruminants and perspectives for human immunotherapy

Gamma-delta (γδ) T cells, which bridge innate and adaptive immunity, are attractive candidates for immunotherapy. Significant interspecies differences exist, particularly between humans and ruminants. In ruminants, γδ T cells are a major circulating population characterized by the Workshop Cluster 1 (WC1) family, a unique set of Scavenger Receptor Cysteine-Rich (SRCR) co-receptors. WC1 molecules function dually as pattern recognition receptors (PRRs) and essential co-stimulators for the γδ T cell receptor (TCR). Specific WC1 isoforms (e.g. WC1.1+, WC1.2+) are associated with distinct functional predispositions, within a broader functional plasticity observed in both human and murine γδ T cell subsets. This review compares human and ruminant γδ T cell biology, proposing the WC1 co-stimulatory system as a functional paradigm for next-generation human T cell therapies. "WC1-inspired" synthetic receptors could provide more physiological, sustained activation, potentially overcoming key therapeutic limitations such as antigen escape and severe toxicity. Despite translational challenges, including the lack of a direct human WC1 ortholog, the ruminant model provides a critical potential for designing more durable and context-responsive immunotherapies.