CD1d-γδ T Cell Receptor Interaction: Adaptations and Function in Tissue Immunity

Tissue resident lymphocytes are critical sentinels of tissue homeostasis, capable of producing rapid memory responses upon detection of pathogens or stress. In humans, T cells bearing a Vδ1 TCR comprise a major portion of this tissue resident memory population. Despite this, their function and the role of antigen specificity in tissues remains largely unknown. In this work, CD1d was leveraged as a known Vδ1 TCR antigen to define and manipulate populations of αβ and γδ T cells. In the setting of umbilical cord blood and lung, CD1d-lipid antigen recognition critically delineated functional outcomes of T cells. CD1d-autoreactive T cells filled apparently opposing roles in asthma, either tissue repair or cytolytic effector function, depending on the immunogenicity of the self-lipids presented by CD1d. In separate but related studies, recently evolved features of γδ TCR constant region dampened TCR signal strength and reduced clonal expansion in vivo. Taken together, these results suggest that CD1d auto-reactivity—and more broadly, self-reactivity—by some T cells is an intrinsic feature of the TCR and could be important for detecting dysbiosis and maintaining tissue homeostasis.