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Direct interaction of Vδ7 TCRs with IL17RA drives the differentiation of TH1-like γδT cells.

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Title:	Direct interaction of Vδ7 TCRs with IL17RA drives the differentiation of TH1-like γδT cells.
Authors:	Ye, Kewei (AUTHOR), Francis, Nimmy (AUTHOR), Dunst, Josefine (AUTHOR), Borgenstam, Amanda (AUTHOR), Rocamonde-Lago, Iris (AUTHOR), Köhler, Stefanie (AUTHOR), You, Yuanyuan (AUTHOR), Dubnovitsky, Anatoly (AUTHOR), Kramer, Anja (AUTHOR), Meng, Fanxi (AUTHOR), Zollner, Valentin (AUTHOR), Vogg, Lisa (AUTHOR), Ryan, Tomás J. (AUTHOR), Hanada, Ken-ichi (AUTHOR), Regen, Tommy (AUTHOR), Waisman, Ari (AUTHOR), Malmström, Vivianne (AUTHOR), Benson, Erik (AUTHOR), Kisielow, Jan (AUTHOR), Krey, Thomas (AUTHOR)
Source:	Science. 7/16/2026, Vol. 393 Issue 6808, p1-18. 18p.
Abstract:	Of the three classes of lymphocytes that constitute the adaptive immune system, γδT cells are the only class for which the principles of antigen recognition remain enigmatic. Although endogenous γδT cell antigen receptor (γδTCR) ligands are thought to regulate γδT cell development, their identities are largely elusive. Here, we identified the interleukin 17 receptor A chain (IL17RA) as a γδTCR ligand that drove the differentiation of Vδ7+ γδT cells with a T helper 1 (TH1)–like effector program in mice. IL17RA promoted this differentiation through an interaction involving germline-encoded regions of the Vδ7 chain, enabling the selection of cells with a diverse CDR3 repertoire and thus acting as a nonclonotypic γδTCR ligand. Together with the nonclonotypic mode of γδTCR engagement by butyrophilins, these results suggest that such interactions represent a general biological mechanism shaping the γδT cell compartment. Editor's summary: The molecules that stimulate the development and function of γδT cells, a type of nonconventional adaptive immune cell, are not well characterized. In addition to recognizing ligands through a variable region, the γδT cell receptor (γδTCR) can interact with proteins through regions encoded in the germline, a type of innate-like recognition that is also called a nonclonogenic interaction. Ye et al. performed a screen to identify ligands for γδTCRs belonging to mice. The interleukin-17 receptor A chain bound to the majority of Vγ4Vδ7 TCRs, and the germline-encoded sequences in Vδ7 were a key determinant of the interaction. This receptor governed the development, maturation, and homeostasis of T helper 1–like γδT cells, helping to shape the γδT cell compartment in mice. —Sarah H. Ross INTRODUCTION: In stark contrast to B cells and αβT cells, γδT cells are the only class of adaptive lymphocytes for which the principles of antigen recognition remain enigmatic. Although the nature of antigens recognized by γδT cells is largely elusive, multiple lines of evidence suggest that endogenous ligands stimulate γδT cell antigen receptors (γδTCRs) to drive the differentiation of effector γδT cell subsets. Although several such molecules have been identified, in most cases, the existence of these ligands remains speculative, and the majority of γδTCRs remain orphan receptors. Recently, several butyrophilin family members were shown to regulate large γδT cell subsets in a nonclonotypic manner, i.e., through interactions with germline-encoded sequences of Vγ chains. However it remained unclear whether this nonclonotypic mode of interaction is unique to butyrophilins or if it represents a more general mechanism shaping the γδT cell compartment. RATIONALE: To study the recognition of endogenous ligands by γδTCRs, we assessed the reactivity of a panel of murine γδTCRs against cell lines representing various components of the thymic microenvironment and sought to identify ligands for them. RESULTS: Multiple γδTCRs displayed strong reactivity to one or more of the cell lines, with distinct activation patterns that could not be explained by recognition of previously known γδTCR ligands. This indicated that a large fraction of γδT cells recognized a diverse set of unknown endogenous molecules that did not belong to previously known classes of γδTCR ligands. Using a cDNA library screen, we identified interleukin 17 receptor A (IL17RA), a proinflammatory cytokine receptor chain not previously implicated in γδTCR signaling, as a ligand for two of these TCRs. Further analysis revealed that a large population of γδT cells in mouse secondary lymphoid organs exhibited IL17RA reactivity. These IL17RA-reactive γδT cells had a highly diverse repertoire of CDR3 loops [junctions formed by V(D)J recombination] but invariably used Vδ7 in their TCRs. Further experiments demonstrated that whereas both CDR3 loops and Vγ chains could modulate IL17RA reactivity, germline-encoded sequences in Vδ7 were its principal determinants, indicating that IL17RA functions as a nonclonotypic ligand for Vδ7 γδTCRs. Analysis of Il17ra−/− mice showed that IL17RA was required for thymic selection, induction of an interferon γ–secreting T helper 1 (TH1)–like effector program, and peripheral homeostatic proliferation of Vδ7+ γδT cells. CONCLUSION: Our results show that the development of a large TH1-like γδT cell subset found in mouse secondary lymphoid organs is driven by direct recognition of IL17RA by Vδ7 γδTCRs. Thus, beyond its role as a cytokine receptor, IL17RA has a second, previously unrecognized function in the immune system as a nonclonotypic TCR ligand. Together with the nonclonotypic mode of γδTCR engagement by butyrophilins, these results suggest that such interactions represent a more general biological principle underlying the organization of the γδT cell compartment than previously anticipated. Such selection on nonclonotypic ligands may have evolved as a mechanism to select and induce the functional maturation of large γδT cell subsets while ensuring high clonal diversity in the resulting effector populations. Nonclonotypic interaction of Vδ7 TCRs with IL17RA drives the generation of a TH1-like γδT cell subset with a diverse CDR3 repertoire.: Left: schematic representation of the IL17RA-Vδ7 γδTCR interaction. Middle, right: in wild-type but not Il17ra-deficient mice, interaction of Vδ7 γδTCRs with IL17RA drives the selection of a large subset of Vδ7+ γδT cells with a diverse CDR3 repertoire (depicted by different colors of CDR3 loops), induces a TH1-like effector program (including up-regulation of the transcription factor Tbet), and promotes IL17RA-dependent peripheral homeostatic proliferation of these cells. [ABSTRACT FROM AUTHOR]
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Database:	Psychology and Behavioral Sciences Collection

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Abstract:	Of the three classes of lymphocytes that constitute the adaptive immune system, γδT cells are the only class for which the principles of antigen recognition remain enigmatic. Although endogenous γδT cell antigen receptor (γδTCR) ligands are thought to regulate γδT cell development, their identities are largely elusive. Here, we identified the interleukin 17 receptor A chain (IL17RA) as a γδTCR ligand that drove the differentiation of Vδ7+ γδT cells with a T helper 1 (TH1)–like effector program in mice. IL17RA promoted this differentiation through an interaction involving germline-encoded regions of the Vδ7 chain, enabling the selection of cells with a diverse CDR3 repertoire and thus acting as a nonclonotypic γδTCR ligand. Together with the nonclonotypic mode of γδTCR engagement by butyrophilins, these results suggest that such interactions represent a general biological mechanism shaping the γδT cell compartment. Editor's summary: The molecules that stimulate the development and function of γδT cells, a type of nonconventional adaptive immune cell, are not well characterized. In addition to recognizing ligands through a variable region, the γδT cell receptor (γδTCR) can interact with proteins through regions encoded in the germline, a type of innate-like recognition that is also called a nonclonogenic interaction. Ye et al. performed a screen to identify ligands for γδTCRs belonging to mice. The interleukin-17 receptor A chain bound to the majority of Vγ4Vδ7 TCRs, and the germline-encoded sequences in Vδ7 were a key determinant of the interaction. This receptor governed the development, maturation, and homeostasis of T helper 1–like γδT cells, helping to shape the γδT cell compartment in mice. —Sarah H. Ross INTRODUCTION: In stark contrast to B cells and αβT cells, γδT cells are the only class of adaptive lymphocytes for which the principles of antigen recognition remain enigmatic. Although the nature of antigens recognized by γδT cells is largely elusive, multiple lines of evidence suggest that endogenous ligands stimulate γδT cell antigen receptors (γδTCRs) to drive the differentiation of effector γδT cell subsets. Although several such molecules have been identified, in most cases, the existence of these ligands remains speculative, and the majority of γδTCRs remain orphan receptors. Recently, several butyrophilin family members were shown to regulate large γδT cell subsets in a nonclonotypic manner, i.e., through interactions with germline-encoded sequences of Vγ chains. However it remained unclear whether this nonclonotypic mode of interaction is unique to butyrophilins or if it represents a more general mechanism shaping the γδT cell compartment. RATIONALE: To study the recognition of endogenous ligands by γδTCRs, we assessed the reactivity of a panel of murine γδTCRs against cell lines representing various components of the thymic microenvironment and sought to identify ligands for them. RESULTS: Multiple γδTCRs displayed strong reactivity to one or more of the cell lines, with distinct activation patterns that could not be explained by recognition of previously known γδTCR ligands. This indicated that a large fraction of γδT cells recognized a diverse set of unknown endogenous molecules that did not belong to previously known classes of γδTCR ligands. Using a cDNA library screen, we identified interleukin 17 receptor A (IL17RA), a proinflammatory cytokine receptor chain not previously implicated in γδTCR signaling, as a ligand for two of these TCRs. Further analysis revealed that a large population of γδT cells in mouse secondary lymphoid organs exhibited IL17RA reactivity. These IL17RA-reactive γδT cells had a highly diverse repertoire of CDR3 loops [junctions formed by V(D)J recombination] but invariably used Vδ7 in their TCRs. Further experiments demonstrated that whereas both CDR3 loops and Vγ chains could modulate IL17RA reactivity, germline-encoded sequences in Vδ7 were its principal determinants, indicating that IL17RA functions as a nonclonotypic ligand for Vδ7 γδTCRs. Analysis of Il17ra−/− mice showed that IL17RA was required for thymic selection, induction of an interferon γ–secreting T helper 1 (TH1)–like effector program, and peripheral homeostatic proliferation of Vδ7+ γδT cells. CONCLUSION: Our results show that the development of a large TH1-like γδT cell subset found in mouse secondary lymphoid organs is driven by direct recognition of IL17RA by Vδ7 γδTCRs. Thus, beyond its role as a cytokine receptor, IL17RA has a second, previously unrecognized function in the immune system as a nonclonotypic TCR ligand. Together with the nonclonotypic mode of γδTCR engagement by butyrophilins, these results suggest that such interactions represent a more general biological principle underlying the organization of the γδT cell compartment than previously anticipated. Such selection on nonclonotypic ligands may have evolved as a mechanism to select and induce the functional maturation of large γδT cell subsets while ensuring high clonal diversity in the resulting effector populations. Nonclonotypic interaction of Vδ7 TCRs with IL17RA drives the generation of a TH1-like γδT cell subset with a diverse CDR3 repertoire.: Left: schematic representation of the IL17RA-Vδ7 γδTCR interaction. Middle, right: in wild-type but not Il17ra-deficient mice, interaction of Vδ7 γδTCRs with IL17RA drives the selection of a large subset of Vδ7+ γδT cells with a diverse CDR3 repertoire (depicted by different colors of CDR3 loops), induces a TH1-like effector program (including up-regulation of the transcription factor Tbet), and promotes IL17RA-dependent peripheral homeostatic proliferation of these cells. [ABSTRACT FROM AUTHOR]
ISSN:	00368075
DOI:	10.1126/science.adx9264