Structural basis of T cell receptor specificity and cross-reactivity of two HLA-DQ2.5-restricted gluten epitopes in celiac disease

Abstract

Celiac disease is a T cell-mediated chronic inflammatory condition often characterized by human leukocyte antigen (HLA)-DQ2.5 molecules presenting gluten epitopes derived from wheat, barley, and rye. Although some T cells exhibit cross-reactivity toward distinct gluten epitopes, the structural basis underpinning such cross-reactivity is unclear. Here, we investigated the T-cell receptor specificity and cross-reactivity of two immunodominant wheat gluten epitopes, DQ2.5-glia-α1a (PFPQPELPY) and DQ2.5-glia-ω1 (PFPQPEQPF). We show by surface plasmon resonance that a T-cell receptor alpha variable (TRAV) 4+-T-cell receptor beta variable (TRBV) 29-1+ TCR bound to HLA-DQ2.5-glia-α1a and HLA-DQ2.5-glia-ω1 with similar affinity, whereas a TRAV4- (TRAV9-2+) TCR recognized HLA-DQ2.5-glia-ω1 only. We further determined the crystal structures of the TRAV4+-TRBV29-1+ TCR bound to HLA-DQ2.5-glia-α1a and HLA-DQ2.5-glia-ω1, as well as the structure of an epitope-specific TRAV9-2+-TRBV7-3+ TCR-HLA-DQ2.5-glia-ω1 complex. We found that position 7 (p7) of the DQ2.5-glia-α1a and DQ2.5-glia-ω1 epitopes made very limited contacts with the TRAV4+ TCR, thereby explaining the TCR cross-reactivity across these two epitopes. In contrast, within the TRAV9-2+ TCR-HLA-DQ2.5-glia-ω1 ternary complex, the p7-Gln was situated in an electrostatic pocket formed by the hypervariable CDR3β loop of the TCR and Arg70β from HLA-DQ2.5, a polar network which would not be supported by the p7-Leu residue of DQ2.5-glia-α1a. In conclusion, we provide additional insights into the molecular determinants of TCR specificity and cross-reactivity to two closely-related epitopes in celiac disease. Celiac disease is a T cell-mediated chronic inflammatory condition often characterized by human leukocyte antigen (HLA)-DQ2.5 molecules presenting gluten epitopes derived from wheat, barley, and rye. Although some T cells exhibit cross-reactivity toward distinct gluten epitopes, the structural basis underpinning such cross-reactivity is unclear. Here, we investigated the T-cell receptor specificity and cross-reactivity of two immunodominant wheat gluten epitopes, DQ2.5-glia-α1a (PFPQPELPY) and DQ2.5-glia-ω1 (PFPQPEQPF). We show by surface plasmon resonance that a T-cell receptor alpha variable (TRAV) 4+-T-cell receptor beta variable (TRBV) 29-1+ TCR bound to HLA-DQ2.5-glia-α1a and HLA-DQ2.5-glia-ω1 with similar affinity, whereas a TRAV4- (TRAV9-2+) TCR recognized HLA-DQ2.5-glia-ω1 only. We further determined the crystal structures of the TRAV4+-TRBV29-1+ TCR bound to HLA-DQ2.5-glia-α1a and HLA-DQ2.5-glia-ω1, as well as the structure of an epitope-specific TRAV9-2+-TRBV7-3+ TCR-HLA-DQ2.5-glia-ω1 complex. We found that position 7 (p7) of the DQ2.5-glia-α1a and DQ2.5-glia-ω1 epitopes made very limited contacts with the TRAV4+ TCR, thereby explaining the TCR cross-reactivity across these two epitopes. In contrast, within the TRAV9-2+ TCR-HLA-DQ2.5-glia-ω1 ternary complex, the p7-Gln was situated in an electrostatic pocket formed by the hypervariable CDR3β loop of the TCR and Arg70β from HLA-DQ2.5, a polar network which would not be supported by the p7-Leu residue of DQ2.5-glia-α1a. In conclusion, we provide additional insights into the molecular determinants of TCR specificity and cross-reactivity to two closely-related epitopes in celiac disease. Celiac disease (CeD) is a chronic inflammatory disorder of the small intestine triggered by ingestion of dietary gluten that affects ∼1% of the general population (1Singh P. Arora A. Strand T.A. Leffler D.A. Catassi C. Green P.H. Kelly C.P. Ahuja V. Makharia G.K. Global prevalence of celiac disease: Systematic review and meta-analysis.Clin. Gastroenterol. Hepatol. 2018; 16: 823-836.e2Google Scholar, 2Sollid L.M. Coeliac disease: Dissecting a complex inflammatory disorder.Nat. Rev. Immunol. 2002; 2: 647-655Google Scholar). Celiac disease is restricted to genetically predisposed individuals, with 95% of patients expressing human leukocyte antigen (HLA) HLA-DQ2.5 (encoded by DQA1∗05:01-DQB1∗02:01 alleles) and the remainder HLA-DQ8 (encoded by DQA1∗03:01-DQB1∗03:02 alleles) or HLA-DQ2.2 (encoded by DQA1∗02:01 -DQB1∗02:02 alleles) (1Singh P. Arora A. Strand T.A. Leffler D.A. Catassi C. Green P.H. Kelly C.P. Ahuja V. Makharia G.K. 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Qiao TCR of cells to and clonal and epitope-specific Immunol. 9: Scholar). of across epitopes by the HLA-DQ2.5 is that these a on with Structural insights into immunodominant these structures that to complex, with to as TCR recognition to from TCR to ternary structures of that a residue formed contacts with and position 7 within J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). ternary structure of a TCR DQ2.5-glia-α1a not a residue and recognition was to the a of recognition to as the of the DQ2.5-glia-α1a was not by the in epitope-specific recognition of DQ2.5-glia-α1a and such as the by between the and J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). In further we that with of these gliadin epitopes J. Ciacchi L. M.Y. Z. J. T receptor cross-reactivity between gliadin and peptides in celiac disease.Nat. Mol. 2020; Scholar). structural to that molecular cross-reactivity in as the TCR recognition on a as in some T cell-mediated J. Ciacchi L. M.Y. Z. J. T receptor cross-reactivity between gliadin and peptides in celiac disease.Nat. Mol. 2020; Scholar, D.A. A. D.A. C.P. J. by a T receptor in of and Exp. Med. Scholar, M. P. R. G. R. T cell-mediated disease to to 2009; Scholar, G. B. A. P. A. A. T receptor and Clin. Invest. Scholar). small of and in patients Ciacchi L. J. A. Lundin K.E. Qiao S.-W. J. T-cell receptor recognition of gluten Scholar, J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar, L. A. V. Lundin K.E. Sollid L. Qiao TCR of cells to and clonal and epitope-specific Immunol. 9: Scholar). was in DQ2.5-glia-α1a and as well as that these epitopes. In that of barley and rye from T toward wheat and and peptides M.Y. Russell A.K. Pizzey C. Jones C.M. Watson K.A. La Gruta N.L. Cameron D.J. Tye-Din J.A. 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Qiao S.-W. J. T-cell receptor recognition of gluten Scholar, R. M.F. B. Lundin K.E. a T and CDR3β Scholar, M.Y. A. Pizzey C. Cameron D.J. Watson K.A. R. L. C. La Gruta N.L. in T-cell to gluten between children and with celiac Scholar). Here, we and TCR recognition of gliadin CD4+ from and cells in and of patients Ciacchi L. J. A. Lundin K.E. Qiao S.-W. J. T-cell receptor recognition of gluten Scholar). We show that limited CDR3β contacts with the variable residue of similar epitopes TCR In contrast, epitope-specific recognition on the electrostatic the provide molecular into TCR cross-reactivity and specificity toward gluten epitopes in We TCR to DQ2.5-glia-ω1 and DQ2.5-glia-α1a and two and that which in a Ciacchi L. J. A. Lundin K.E. Qiao S.-W. J. T-cell receptor recognition of gluten TCR was derived from a T that reactivity to DQ2.5-glia-α1a and HLA-DQ2.5-glia-ω1 and derived from T cells of two patients and that with the HLA-DQ2.5-glia-ω1 not with the HLA-DQ2.5-glia-α1a of T and loop with DQ2.5-glia-α1a and in Ciacchi L. J. A. Lundin K.E. Qiao S.-W. J. T-cell receptor recognition of gluten Scholar). was from J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). of gluten epitopes L.M. Tye-Din J.A. Qiao S.-W. C. F. and of celiac gluten epitopes recognized by CD4+ T 2020; Scholar). as DQ2.5-glia-α1a in and DQ2.5-glia-ω1 of the to TCR as and with DQ2.5-glia-α1a in a and in Ciacchi L. J. A. Lundin K.E. Qiao S.-W. J. T-cell receptor recognition of gluten Scholar). was from J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). of gluten epitopes L.M. Tye-Din J.A. Qiao S.-W. C. F. and of celiac gluten epitopes recognized by CD4+ T 2020; Scholar). as DQ2.5-glia-α1a in and DQ2.5-glia-ω1 of the to TCR as and further the specificity of the TCR, we a of the DQ2.5-glia-α1a and HLA-DQ2.5-glia-ω1 epitopes with the in a epitopes, the reactivity to peptides and whereas of the and from HLA-DQ2.5-glia-α1a and HLA-DQ2.5-glia-ω1 cells in we surface plasmon resonance on TCR, and determined and and and of of of is the the is the the of the from or or of from to a and the and in a of is the the is the the of the from or or of from to a and the and TCR with HLA-DQ2.5-glia-ω1 and with a of the TCR bound HLA-DQ2.5-glia-ω1 Ciacchi L. J. A. Lundin K.E. Qiao S.-W. J. T-cell receptor recognition of gluten Scholar). the TCR bound the was the and distinct with HLA-DQ2.5-glia-ω1, on and and to of and and and TCR bound to HLA-DQ2.5-glia-α1a and HLA-DQ2.5-glia-ω1 with with of and of the TCR that of the TCR to HLA-DQ2.5-glia-α1a we Ciacchi L. J. A. Lundin K.E. Qiao S.-W. J. T-cell receptor recognition of gluten Scholar). the of the bound to as and the of the and and and that the variable residue is the and of the the molecular basis recognition of we determined the crystal structure of the TRAV9-2+-TRBV7-3+ TCR-HLA-DQ2.5-glia-ω1 complex to and We the structure of the TRAV4+ TCR in complex with HLA-DQ2.5-glia-α1a to which was restricted J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). to the TCR ternary the TCR an of across the of HLA-DQ2.5 with surface of TCR and HLA-DQ2.5 and and Gruta N.L. J. the of of T Rev. Immunol. 2018; Scholar). to the of the TCR and CDR3β and whereas the and and of the TCR with and of Here, the and made limited contacts with the HLA-DQ2.5 with the of the TCR a between TCR HLA-DQ2.5 and additional with the HLA-DQ2.5 and by and a basis of the toward the HLA-DQ2.5-glia-ω1 loop formed a with the HLA-DQ2.5 In contrast, the CDR3β loop of TCR formed with the HLA-DQ2.5 by CDR3β and with HLA-DQ2.5 and Arg70β and a between the CDR3β residue of the TCR was formed with Arg70β of HLA-DQ2.5 the p7-Gln of the the position of Arg70β from that of the HLA-DQ2.5-glia-ω1 structure Ciacchi L. J. A. Lundin K.E. Qiao S.-W. J. T-cell receptor recognition of gluten Scholar). Arg70β in the TCR-HLA-DQ2.5-glia-ω1 complex into the and with to the polar network p7-Gln polar network by the CDR3β loop and Arg70β with p7-Gln would be by the p7-Leu of thereby a basis as to the TCR DQ2.5-glia-α1a. In of HLA-DQ2.5-glia-α1a recognition by the TCR not on CDR3β and Arg70β with p7-Leu residue Ciacchi L. J. A. Lundin K.E. Qiao S.-W. J. T-cell receptor recognition of gluten Scholar, J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). TCR and of the DQ2.5-glia-ω1 Here, the of and the and the of p7-Gln TCR recognition of DQ2.5-glia-ω1 as with the position was Ciacchi L. J. A. Lundin K.E. Qiao S.-W. J. T-cell receptor recognition of gluten Scholar). the of the p7-Gln to the of the CDR3β specificity of the TCR DQ2.5-glia-ω1 was to polar contacts with p7-Gln that be formed with p7-Leu of the DQ2.5-glia-α1a the structural that cross-reactivity across the DQ2.5-glia-α1a and DQ2.5-glia-ω1 epitopes, we the ternary structures of the TRAV4+-TRBV29-1+ TCR bound to HLA-DQ2.5-glia-α1a and HLA-DQ2.5-glia-ω1 to and two ternary very similar to and we the within the TRAV4+-TRBV29-1+ complex and to the TRAV4+-TRBV29-1+ TCR-HLA-DQ2.5-glia-ω1 ternary complex. TCR on an of with an of the and CDR3β and of the whereas and to and of the and ternary of the TCR to provide a structural basis underpinning of the TRAV4+ TCR the of the TCR by and with HLA-DQ2.5 as in the TRAV4+ complex and and and J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). loop with and of HLA-DQ2.5 and and and with HLA-DQ2.5, whereas the hypervariable CDR3β made contacts with the HLA-DQ2.5 and Here, the HLA-DQ2.5 and Arg70β the position of epitopes by TCR and a between CDR3β of TCR was formed with Arg70β from HLA-DQ2.5, that was by contacts between CDR3β and and with and of the HLA-DQ2.5 and and TCR with the DQ2.5-glia-α1a the CDR3β residue of and the and with the and in the CDR3β loop loop contacts with in the TRAV4+ TCR further the of J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). and CDR3β the of In contrast, in the ternary complex, the loop the of from DQ2.5-glia-ω1 the of the DQ2.5-glia-α1a p7-Leu residue was by the of CDR3β p7-Gln of DQ2.5-glia-ω1 was by the of CDR3β from the with of DQ2.5-glia-α1a and DQ2.5-glia-ω1 epitopes and In to the TCR-HLA-DQ2.5-glia-ω1 complex, the p7-Gln residue of complex was not by Arg70β of the HLA-DQ2.5 in the TCR ternary the Arg70β with the TCR and of and the TCR not the electrostatic pocket formed by Arg70β as in the TCR-HLA-DQ2.5-glia-ω1 complex. we the molecular basis antigen recognition of HLA-DQ2.5-glia-α1a and by restricted to these J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). HLA-DQ2.5-glia-α1a restricted TCR limited with DQ2.5-glia-α1a of or In contrast, ternary structures of restricted to the basis the of a CDR3β loop residue with a as a by the and the HLA-DQ2.5 J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). of antigen recognition a to we and in restricted to J. A. A. J. T receptor human leukocyte antigen gliadin peptides is with celiac Scholar, J. M. J. F. J. T receptor in celiac disease into a Scholar). we that to a TCR recognition of these gliadin epitopes. we on to show that T cross-reactivity between peptides and gliadin determinants be a by which pathogenesis is to the we in with to cross-reactivity DQ2.5-glia-α1a and the TCR residue the peptides of TCR J. Ciacchi L. M.Y. Z. J. T receptor cross-reactivity between gliadin and peptides in celiac disease.Nat. Mol. 2020; Scholar). In the we into the molecular basis epitope-specific and TCR recognition of two similar epitopes, DQ2.5-glia-α1a and on of a DQ2.5-glia-α1a TCR, in complex with TCR recognition of TRAV4+ TCR not on p7-Leu such as HLA-DQ2.5 and Arg70β J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). is in to TCR recognition of DQ2.5-glia-ω1 by the TRAV9-2+ TCR that was by with p7-Gln by within the CDR3β DQ2.5-glia-ω1 recognition was characterized by a in Arg70β from HLA-DQ2.5 to with to a polar network of with and polar network would be which a residue the recognition of DQ2.5-glia-α1a by the TCR, not on the of contacts with Arg70β and CDR3β loop of TCR J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). CDR3β loop of the TCR was from the DQ2.5-glia-α1a and HLA-DQ2.5 that the hypervariable CDR3β loop of a the HLA-DQ2.5-glia-ω1 that of TCR with a the of that toward two immunodominant epitopes in Ciacchi L. J. A. Lundin K.E. Qiao S.-W. J. T-cell receptor recognition of gluten Scholar). TCR the TRAV4+ TCR formed limited CDR3β loop contacts with of the DQ2.5-glia-α1a and DQ2.5-glia-ω1 epitopes. the reactivity on DQ2.5-glia-α1a and DQ2.5-glia-ω1 Ciacchi L. J. A. Lundin K.E. Qiao S.-W. J. T-cell receptor recognition of gluten the residue was not recognition by the T that cross-reactivity is the TRAV4+ TCR or to the TRAV4+ TCR, the Arg70β is from of and with the TCR and the as the and the ternary of and of HLA-DQ2.5-glia-α1a the CDR3β loop of formed with of DQ2.5-glia-α1a and HLA-DQ2.5 that in the ternary complex. the CDR3β loop of with DQ2.5-glia-α1a in a to the CDR3β of the TCR with p7-Leu of the DQ2.5-glia-α1a as was CDR3β with p7-Leu J. Ciacchi L. M.Y. Z. J. T receptor cross-reactivity between gliadin and peptides in celiac disease.Nat. Mol. 2020; Scholar, J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). the of and on CDR3β the was the the and as CDR3β gluten J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar, Qiao S.-W. Lundin K.E. J. Sollid L.M. J. molecular basis the T in HLA-DQ2.2 celiac Sci. A. 2020; 117: Scholar). the hypervariable CDR3β of the and a in with on molecular that TCR cross-reactivity in the of disease D.A. A. D.A. C.P. J. by a T receptor in of and Exp. Med. Scholar, D.A. of a human TCR is by a TCR Scholar). on between the TCR cross-reactivity M. P. R. G. R. T cell-mediated disease to to 2009; Scholar, D.A. of a human TCR is by a TCR Scholar, C. L. P. L. A. and structural basis TCR cross-reactivity in Immunol. 2002; Scholar, M. J. of complex by a human T Immunol. 2005; Scholar). In of the loop loop to TCR in recognition J. Ciacchi L. M.Y. Z. J. T receptor cross-reactivity between gliadin and peptides in celiac disease.Nat. Mol. 2020; Scholar, J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar, D.A. of a human TCR is by a TCR Scholar, C. C. G. A. B. loop to the of TCR Immunol. Scholar, of hypervariable loop control T-cell receptor and Mol. Scholar, A.K. T receptor cross-reactivity by of molecular 2009; Scholar, L. of an immunodominant T receptor Immunol. 2005; Scholar). Here, the TCR from as the TCR is the between gliadin epitopes. a of TCR cross-reactivity between epitopes in T as Ciacchi L. J. A. Lundin K.E. Qiao S.-W. J. T-cell receptor recognition of gluten Scholar, A. M. Lundin K.E. Jahnsen J. Sollid L.M. Qiao CD4+ T cells in as a coeliac disease gluten Gastroenterol. J. 2: Scholar). and with peptides T cells to the the with was to a is of HLA-DQ2.5 the with gliadin epitopes to the of the HLA-DQ2.5 J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar, Qiao S.-W. Lundin K.E. J. Sollid L.M. J. molecular basis the T in HLA-DQ2.2 celiac Sci. A. 2020; 117: Scholar, J. A. A. J. T receptor human leukocyte antigen gliadin peptides is with celiac Scholar). of gliadin epitopes in the HLA-DQ2.5 as DQ2.5-glia-α1a DQ2.5-glia-ω1 and to HLA-DQ2.5 a J. Ciacchi L. M.Y. Z. J. T receptor cross-reactivity between gliadin and peptides in celiac disease.Nat. Mol. 2020; Scholar, Ciacchi L. J. A. Lundin K.E. Qiao S.-W. J. T-cell receptor recognition of gluten Scholar, J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). was to the HLA-DQ8 a J. A. A. J. T receptor human leukocyte antigen gliadin peptides is with celiac Scholar). In was a a and a to as J. Ciacchi L. M.Y. Z. J. T receptor cross-reactivity between gliadin and peptides in celiac disease.Nat. Mol. 2020; Scholar, J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). into and the cells We cells of as J. Ciacchi L. M.Y. Z. J. T receptor cross-reactivity between gliadin and peptides in celiac disease.Nat. Mol. 2020; Scholar, J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). was and into in with J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar, Tye-Din J.A. Z. A. N.L. structural and basis the of human leukocyte antigen in celiac 2007; Scholar, J. A. A. J. T receptor human leukocyte antigen gliadin peptides is with celiac Scholar). was and was by the was by and the with a of was with in the of TCR and M. M. P. T-cell receptor molecules and 16: in J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar, Qiao S.-W. Lundin K.E. J. Sollid L.M. J. molecular basis the T in HLA-DQ2.2 celiac Sci. A. 2020; 117: Scholar, J. A. A. J. T receptor human leukocyte antigen gliadin peptides is with celiac Scholar, L. J. J. and of a of a T-cell receptor in and 2002; Scholar). αβ from as J. Ciacchi L. M.Y. Z. J. T receptor cross-reactivity between gliadin and peptides in celiac disease.Nat. Mol. 2020; Scholar, J. A. A. J. T receptor human leukocyte antigen gliadin peptides is with celiac Scholar, J. J. A. of T in celiac disease.J. Immunol. Scholar). the TCR and in a and and to the was into to and by and to to in and that from of and the of structures from of to and to structures formed in with of and of In the the ternary complex structures with and as J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar). to 7 in and in the the J. R. M. D.J. the and the 2018; Scholar). was and of the program P. A. of the and Scholar, G. B. structure and in Scholar). structures molecular with structures of by molecular with 2007; from structures of Ciacchi L. J. A. Lundin K.E. Qiao S.-W. J. T-cell receptor recognition of gluten TCR or a model TCR structure from the TCR and of and J. V. M. A. J. T-cell receptor recognition of with celiac disease.Nat. Mol. 21: Scholar, A. P. M. J. J. J. I. T-cell receptor T-cell to and Scholar). and P. B. and of program G. B. structure and in Scholar, structures of by molecular with 2007; Scholar, V. D.A. and structure Sci. 2018; Scholar, M. A. P.H. structure with Scholar, G. structure Scholar). was to the structural plasmon resonance on with a and was as a in with a of HLA-DQ2.5-glia-ω1, and to a of an of of was to the of and the surface in a of with a of to in and the was determined from two or structures in the ternary and that of with the of We the with crystal on the L. C. and L. C. J. and R. L. C. and J. R. C. J. and R. C. J. L. M. and J. R. and and L. M. L. M. and J. R. was supported by the and of and by the and the of the of and and by to L. M. J. R. is supported by an

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