Alternate interactions define the binding of peptides to the MHC molecule IA<sup>b</sup>

Liu, Xinqi; Dai, Shaodong; Crawford, Frances; Frugé, Rachel; Marrack, Philippa; Kappler, John W.

doi:10.1073/pnas.132272099

Cited by 72 publications

(81 citation statements)

References 55 publications

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“…Peptides were eluted from these preparations and subjected to MS or MS-MS analysis as previously reported (32) and as described in Materials and Methods. A preliminary MS-MS analysis of the peptides isolated from WT and mutant I-A b showed that they had I-A bbinding motifs (Table S2) (33,34). This finding served to validate our method of peptide isolation and suggested that the I-A b mutations did not affect the I-A b peptide-binding motif.…”

Section: Mutations Of the I-a B Conserved Amino Acids Affect The Presmentioning

confidence: 58%

Class II major histocompatibility complex mutant mice to study the germ-line bias of T-cell antigen receptors

Silberman

Krovi

Tuttle

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The interaction of αβ T-cell antigen receptors (TCRs) with peptides bound to MHC molecules lies at the center of adaptive immunity. Whether TCRs have evolved to react with MHC or, instead, processes in the thymus involving coreceptors and other molecules select MHC-specific TCRs de novo from a random repertoire is a longstanding immunological question. Here, using nuclease-targeted mutagenesis, we address this question in vivo by generating three independent lines of knockin mice with single-amino acid mutations of conserved class II MHC amino acids that often are involved in interactions with the germ-line-encoded portions of TCRs. Although the TCR repertoire generated in these mutants is similar in size and diversity to that in WT mice, the evolutionary bias of TCRs for MHC is suggested by a shift and preferential use of some TCR subfamilies over others in mice expressing the mutant class II MHCs. Furthermore, T cells educated on these mutant MHC molecules are alloreactive to each other and to WT cells, and vice versa, suggesting strong functional differences among these repertoires. Taken together, these results highlight both the flexibility of thymic selection and the evolutionary bias of TCRs for MHC.T he genes for immunoglobulins (Igs), αβ T-cell receptors (TCRs), and antigen-presenting MHC proteins appeared at least 450 million years ago in the cartilaginous fish and are present in all modern vertebrates (1-3). The more primitive hagfish and lampreys lack these genes and have an adaptive immune system comprised of unrelated proteins (4). The main ligands for αβ TCRs are short peptides derived from self and foreign proteins, captured in a specialized groove of MHC class I (MHCI) and class II (MHCII) molecules and presented to T cells (5, 6). Functional Igs and TCRs are created by very similar recombination mechanisms involving fusion of V, J, and sometimes D gene segments with additional variations at the junctions to create an enormous potential repertoire of Igs and TCRs, suggesting a common, unknown evolutionary origin for these loci.These observations have raised several unanswered questions. For example,why did a separate TCR-rearranging gene system develop for lymphocytes recognizing peptide-MHC ligands? How did the extraordinarily polymorphic MHC genes stay functionally connected to TCR genes throughout 450 million years of evolution? One long-standing hypothesis has been that certain features of TCRs and MHC molecules are evolutionarily conserved to promote their interaction (7-10). Like Igs, the antigen-recognition portions of TCRs are partially encoded in the complementary determining region (CDR) CDR1 and CDR2 loops of germ-line TCR Vα (TRAV) and Vβ (TRBV) genes and are partially generated by somatic recombination processes that form the CDR3 loops. This initial repertoire is culled dramatically during T-cell development in the thymus. First, only those T cells whose TCRs have at least some minimal affinity for the selfpeptide-MHC molecules expressed in the thymus are positively selected for fu...

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Section: Mutations Of the I-a B Conserved Amino Acids Affect The Presmentioning

confidence: 58%

Class II major histocompatibility complex mutant mice to study the germ-line bias of T-cell antigen receptors

Silberman

Krovi

Tuttle

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Several MHC class II molecules (I-A d , I-A k , I-A u , I-A b , and I-A g7 ) (19,20,42,43,45) do have a hydrogen bond between glutamate ␤74 and the P5 amide. The side chain of alanine ␤74 in DQ2 is, however, not a hydrogen bond acceptor.…”

Section: Discussionmentioning

confidence: 99%

Main Chain Hydrogen Bond Interactions in the Binding of Proline-rich Gluten Peptides to the Celiac Disease-associated HLA-DQ2 Molecule

Bergseng

Xia²,

Kim³

et al. 2005

Journal of Biological Chemistry

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Binding of peptide epitopes to major histocompatibility complex proteins involves multiple hydrogen bond interactions between the peptide main chain and major histocompatibility complex residues. The crystal structure of HLA-DQ2 complexed with the ␣I-gliadin epitope (LQPFPQPELPY) revealed four hydrogen bonds between DQ2 and peptide main chain amides. This is remarkable, given that four of the nine core residues in this peptide are proline residues that cannot engage in amide hydrogen bonding. Preserving main chain hydrogen bond interactions despite the presence of multiple proline residues in gluten peptides is a key element for the HLA-DQ2 association of celiac disease. We have investigated the relative contribution of each main chain hydrogen bond interaction by preparing a series of Nmethylated ␣I epitope analogues and measuring their binding affinity and off-rate constants to DQ2. Additionally, we measured the binding of ␣I-gliadin peptide analogues in which norvaline, which contains a backbone amide hydrogen bond donor, was substituted for each proline. Our results demonstrate that hydrogen bonds at P4 and P2 positions are most important for binding, whereas the hydrogen bonds at P9 and P6 make smaller contributions to the overall binding affinity. There is no evidence for a hydrogen bond between DQ2 and the P1 amide nitrogen in peptides without proline at this position. This is a unique feature of DQ2 and is likely a key parameter for preferential binding of proline-rich gluten peptides and development of celiac disease.

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“…MOG37-52 being the optimal minimal stimulatory sequence for 95% of the MOG35-55 T cell clones, it was conceivable that any potential core epitope would be contained within it. Nonameric registers within MOG37-52 with potential binding affinity to I-A b were analyzed by modeling the interaction of MOG37-52 with I-A b , based on the recently available I-A b crystal structure [21]. The modeling data for the MOG37-52/I-A b interaction (Fig.…”

Section: Diverse Tcr V Gene Usage By Mog35-55-specific T Cell Clonesmentioning

confidence: 99%

“…The model of the MOG37-52/A b interaction with MOG40-48 as the core epitope (Fig. 1A) positioned residues R41, S42, F44, R46 and V47 in pockets p2, p3, p5, p7 and p8, respectively, as potential TCR interacting residues, with residues MOG41R and MOG44F in p2 and p5 predicted to be the more crucial according to the available structure of the TCR-MHC class II-peptide complex [21]. These predictions were recently corroborated experimentally [26,27].…”

Section: Mog37-52-reactive Clones Expressing Highly Heterogeneous Tcrmentioning

confidence: 99%

“…The X-ray structure of the MHC class II I-A b molecule [21] with bound peptide (entry 1lnu in the Protein Data Bank) was used in order to identify the core epitope within MOG37-52. Analysis of the structure of I-A b in terms of the size and chemical character of the binding cavities, which accommodate the nonapeptide side chains, facilitated the construction of a 9 Â 20 binding preference matrix for this MHC molecule.…”

Section: Molecular Modelingmentioning

confidence: 99%

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Anatomy of T cell autoimmunity to myelin oligodendrocyte glycoprotein (MOG): Prime role of MOG44F in selection and control of MOG‐reactive T cells in H‐2^b mice

et al. 2006

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Myelin oligodendrocyte glycoprotein (MOG) is an important myelin target antigen, and MOG-induced EAE is now a widely used model for multiple sclerosis. Clonal dissection revealed that MOG-induced EAE in H-2 b mice is associated with activation of an unexpectedly large number of T cell clones reactive against the encephalitogenic epitope MOG35-55. These clones expressed extremely diverse TCR with no obvious CDR3a/ CDR3b motif(s). Despite extensive TCR diversity, the cells required MOG40-48 as their common core epitope and shared MOG44F as their major TCR contact. Fine epitopespecificity analysis with progressively truncated peptides suggested that the extensive TCR heterogeneity is mostly related to differential recognition of multiple overlapping epitopes nested within MOG37-52, each comprised of a MOG40-48 core flanked at the N-and/or the C-terminus by a variable number of residues important for interaction with different TCR. Abrogation of both the encephalitogenic potential of MOG and T cell reactivity against MOG by a single mutation (MOG44F/MOG44A), together with effective down-regulation of MOG-induced EAE by MOG37-44A-52, confirmed in vivo the primary role for MOG44F in the selection/activation of MOG-reactive T cells. We suggest that such a highly focused T cell autoreactivity could be a selective force that offsets the extensive TCR diversity to facilitate a more "centralized control" of pathogenic MOG-related T cell autoimmunity.

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Alternate interactions define the binding of peptides to the MHC molecule IA^b

Cited by 72 publications

References 55 publications

Class II major histocompatibility complex mutant mice to study the germ-line bias of T-cell antigen receptors

Class II major histocompatibility complex mutant mice to study the germ-line bias of T-cell antigen receptors

Main Chain Hydrogen Bond Interactions in the Binding of Proline-rich Gluten Peptides to the Celiac Disease-associated HLA-DQ2 Molecule

Anatomy of T cell autoimmunity to myelin oligodendrocyte glycoprotein (MOG): Prime role of MOG44F in selection and control of MOG‐reactive T cells in H‐2^b mice

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Alternate interactions define the binding of peptides to the MHC molecule IAb

Cited by 72 publications

References 55 publications

Class II major histocompatibility complex mutant mice to study the germ-line bias of T-cell antigen receptors

Class II major histocompatibility complex mutant mice to study the germ-line bias of T-cell antigen receptors

Main Chain Hydrogen Bond Interactions in the Binding of Proline-rich Gluten Peptides to the Celiac Disease-associated HLA-DQ2 Molecule

Anatomy of T cell autoimmunity to myelin oligodendrocyte glycoprotein (MOG): Prime role of MOG44F in selection and control of MOG‐reactive T cells in H‐2b mice

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Alternate interactions define the binding of peptides to the MHC molecule IA^b

Anatomy of T cell autoimmunity to myelin oligodendrocyte glycoprotein (MOG): Prime role of MOG44F in selection and control of MOG‐reactive T cells in H‐2^b mice