Coexpression of αβ and γδ TCRs bridges innate and adaptive immunity

Lymphocytes are defined by the type of antigen receptor expressed; B lymphocytes express membrane-bound immunoglobulin B cell receptor, while T lymphocytes express a T cell receptor (TCR). The majority of T cells express a canonical αβTCR, which recognizes peptide antigens presented by major histocompatibility complex (MHC) molecules to mediate cytotoxic or helper cell responses. A subset of T cells instead expresses a γδTCR, which interacts with non-MHC–restricted ligands. γδ T cells have innate immune–like function, with distinct kinetic, anatomic, and effector features.

In contrast to the notion that αβ and γδ T cells are independent lineages, Edwards et al. report discovery of T cells that coexpress αβ and γδ TCRs. Using flow cytometry and confocal microscopy, they identified ~7 to 10% of human and mouse γδ T cells as coexpressing αβ TCRs. These αβ-γδ cells developed in the thymus and possessed a diverse array of αβTCR clonotypes with a limited repertoire of γδTCRs. Both TCRs were independently functional, and αβ-γδ cells responded to interleukin-1β (IL-1β) and IL-23, cytokines that stimulate innate-like responses in γδ T cells. Transcriptional profiling demonstrated αβ-γδ cells have shared features with, but are distinct from, both conventional αβ and γδ T cells. Signaling pathways associated with production of IL-17 by both γδ (Sox13) and αβ (Rorc) T cells were active in αβ-γδ cells, and TCR stimulation modulated cytokine production, indicating potential integration of αβ and γδ functions.

The hybrid nature of αβ-γδ cells underlies their pathogenic ability in a mouse model of autoimmunity, experimental autoimmune myelitis (EAE). Immunization with myelin oligodendrocyte protein autoantigen expanded αβ-γδ cells with autoreactive αβTCRs. Autoreactive αβTCR-expressing αβ-γδ cells were the predominant T cell in the central nervous system during the first 3 days of EAE development, driven by expression of γδ T cell–associated chemokine receptors CCR2 and CCR6 and trafficking molecule CD49d. These findings demonstrate αβ-γδ T cells as uniquely combining innate-like immune effector and migration responses with conventional T cell specificity in autoimmunity and identify a potential link between innate and adaptive immunity. This study demonstrates a role for αβ-γδ cells in mouse autoimmunity and their presence in humans, although their function in human autoimmune disease remains to be explored.

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