Abstract
T lymphocytes expressing γδ T cell antigen receptors (TCRs) comprise evolutionarily conserved cells with paradoxical features. On the one hand, clonally expanded γδ T cells with unique specificities typify adaptive immunity. Conversely, large compartments of γδTCR+ intraepithelial lymphocytes (γδ IELs) exhibit limited TCR diversity and effect rapid, innate-like tissue surveillance. The development of several γδ IEL compartments depends on epithelial expression of genes encoding butyrophilin-like (Btnl (mouse) or BTNL (human)) members of the B7 superfamily of T cell co-stimulators. Here we found that responsiveness to Btnl or BTNL proteins was mediated by germline-encoded motifs within the cognate TCR variable γ-chains (Vγ chains) of mouse and human γδ IELs. This was in contrast to diverse antigen recognition by clonally restricted complementarity-determining regions CDR1-CDR3 of the same γδTCRs. Hence, the γδTCR intrinsically combines innate immunity and adaptive immunity by using spatially distinct regions to discriminate non-clonal agonist-selecting elements from clone-specific ligands. The broader implications for antigen-receptor biology are considered.
Highlights
Adaptive immunity in jawed vertebrates is underpinned by the use of somatic gene rearrangement to diversify three conserved lineages of lymphocytes: αβ T cells, B cells and γδ T cells[1]
The T cell receptor (TCR) specificities of rare or unique mouse and human γδ T cells are seemingly enriched in self-encoded ligands, several of which are closely related to Major Histocompatibility Complex (MHC) proteins[6, 7, 8, 9, 10, 11]
Murine TCRVγ7 mediates Btnl-responsiveness The signature intestinal γδ IEL compartment is dominated by Vγ7+ cells, whose development is severely impaired in Btnl1-/- mice[22]
Summary
Adaptive immunity in jawed vertebrates is underpinned by the use of somatic gene rearrangement to diversify three conserved lineages of lymphocytes: αβ T cells, B cells and γδ T cells[1]. Microbe-specific γδ T cells have proved largely elusive. Human peripheral blood γδ T cells make generic responses to microbes by recognizing hydroxymethylbut-2-enyl pyrophosphate (HMBPP), an intermediate in sterol metabolism that is more akin to a pathogen-associated molecular pattern[5]. The TCR specificities of rare or unique mouse and human γδ T cells are seemingly enriched in self-encoded ligands, several of which are closely related to Major Histocompatibility Complex (MHC) proteins[6, 7, 8, 9, 10, 11]. Until the biological significance of such specificities is established, the host benefits of adaptive γδ TCR diversification will remain unresolved
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