The impact of HLA‐B micropolymorphism outside primary peptide anchor pockets on the CTL response to CMV

Burrows, Jacqueline M.; Wynn, Katherine K.; Tynan, Fleur Elizabeth; Archbold, J.K.; Miles, John J.; Bell, Melissa J.; Brennan, Rebekah; Walker, Susan; McCluskey, James; Rossjohn, Jamie; Khanna, Rajiv; Burrows, Scott R.

doi:10.1002/eji.200636588

Cited by 44 publications

(38 citation statements)

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“…Although these experiments indicated that both the FPT and CPS epitopes bind to HLA B*3508 with equal efficiency, our recent studies have shown that the dissociation half-life for B*3508 CPS and B*3508 FPT complexes was 37.1 hours and 21.1 hours, respectively. 22 Taken together, these observations suggested the differences in the disassociation kinetics of the CPS and FPT epitopes for HLA B*3508 directly impacts on their antigen presentation efficiency in HCMV-infected cells, which was consistent with our previously documented evidence on the impact of pMHC binding on determinant selection. 27 …”

Section: Tcr Selection Correlates With Functional Properties Of Cps-asupporting

confidence: 91%

“…22 This is illustrated by HLA B35-restricted CD8 ϩ T-cell responses to the pp65 epitopes, CPSQEPMSIYVY and FPTKDVAL (herein referred to as CPS and FPT, respectively), which are exclusively recognized by HLA B*3508 ϩ individuals, while HLA B*3501 ϩ , HLA B*3503 ϩ , and HLA B35 Ϫ donors showed no significant ex vivo response to these epitopes ( Figure 1A). These observations were also confirmed by in vitro stimulation of T cells, which showed that these epitopes selectively expanded T cells from HLA B*3508 ϩ individuals ( Figure 1B).…”

Section: Cd8 ؉ T Cells Specific For Hcmv Epitopes Restricted Through mentioning

confidence: 99%

“…These epitopes, the noncanonical 103 CPSQEPM-SIYVY 111 (CPS) and the canonical 188 FPTKDVAL 195 (FPT), are restricted through HLA B*3508. 22 Given that these 2 epitopes are highly immunogenic, derived from the same antigenic source, and restricted through the identical MHC alleles, this model provides an ideal opportunity to investigate the role of pMHC in shaping the TCR repertoire. Here, we present evidence that competing levels of endogenous epitope presentation is pivotal in shaping the T-cell repertoire during a persistent viral infection.…”

Section: Introductionmentioning

confidence: 99%

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Impact of clonal competition for peptide-MHC complexes on the CD8+ T-cell repertoire selection in a persistent viral infection

Wynn

Fulton

Cooper

et al. 2008

Blood

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CD8 ؉ T-cell responses to persistent viral infections are characterized by the accumulation of an oligoclonal T-cell repertoire and a reduction in the naive T-cell pool. However, the precise mechanism for this phenomenon remains elusive. Here we show that human cytomegalovirus (HCMV)-specific CD8 ؉ T cells recognizing distinct epitopes from the pp65 protein and restricted through an identical HLA class I allele (HLA B*3508) exhibited either a highly conserved public Tcell repertoire or a private, diverse T-cell response, which was uniquely altered in each donor following in vitro antigen exposure. Selection of a public T-cell receptor (TCR) was coincident with an atypical major histocompatibility complex (MHC)-peptide structure, in that the epitope adopted a helical conformation that bulged from the peptide-binding groove, while a diverse TCR profile was observed in response to the epitope that formed a flatter, more "featureless" landscape. Clonotypes with biased TCR usage demonstrated more efficient recognition of virus-infected cells, a greater CD8 dependency, and were more terminally differentiated in their phenotype when compared with the T cells expressing diverse TCR. These findings provide new insights into our understanding on how the biology of antigen presentation in addition to the structural features of the pMHC-I might shape the T-cell repertoire and its pheno- IntroductionThe ␣␤ T-cell receptor (TCR) recognizes immunogenic peptides in association with the major histocompatibility complex (pMHC) on the surface of virus-infected cells. 1,2 Upon recognition of foreign antigen, the naive T-cell repertoire responds to produce either polyclonal, oligoclonal, or clonal immune responses. The diversity of the TCR repertoire is created primarily due to differences in the sequence of the hypervariable complementarity determining region 3 (CDR3) of each chain of the TCR. 3,4 The CDR3 loops are formed at the junction of the V(D)J gene segments as a result of random nucleotide addition and removal during the gene rearrangement process in the thymus. 5,6 Numerous factors shape the T-cell repertoire, including thymic selection of the naive T-cell repertoire, TCR avidity for the pMHC complex, antigen load, and duration of the pMHC-TCR interaction. [7][8][9][10] However, the relative contribution of these in shaping the TCR repertoire remains unclear.TCR repertoire selection is also complicated by MHC class I-restricted T cells interacting with peptides of noncanonical and canonical length. Typically, noncanonical peptides of more than 10 amino acids in length bulge from the peptide-binding cleft, [11][12][13][14][15][16][17] and this unusual feature can result in biased selection of the TCR repertoire, suggesting the structure of the pMHC complex plays an important role in shaping the TCR repertoire. Conversely, featureless canonical 8-to 9-amino acid long epitopes from both persistent and nonpersistent viruses can also induce a highly biased T-cell repertoire. [18][19][20][21] Collectively, these studies highlig...

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Section: Tcr Selection Correlates With Functional Properties Of Cps-asupporting

confidence: 91%

Section: Cd8 ؉ T Cells Specific For Hcmv Epitopes Restricted Through mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impact of clonal competition for peptide-MHC complexes on the CD8+ T-cell repertoire selection in a persistent viral infection

Wynn

Fulton

Cooper

et al. 2008

Blood

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“…This has only been reported within a narrow slice of the Vβ repertoire, where consensus Vβ8.2 + CDR2β-mediated interactions were observed with closely related pMHC-II molecules (6,7). It is also suggested that the same V region can potentially interact with dis- (36), and RL16 (34,37). These experiments were independently performed twice for clones LC13, GL3, and CFB40, with analogous results on each occasion.…”

Section: Discussionmentioning

confidence: 82%

Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability

Burrows

Chen

Archbold

et al. 2010

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

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αβ T cell receptors (TCRs) are genetically restricted to corecognize peptide antigens bound to self-major histocompatibility complex (pMHC) molecules; however, the basis for this MHC specificity remains unclear. Despite the current dogma, evaluation of the TCR-pMHC-I structural database shows that the nongermline-encoded complementaritydetermining region (CDR)-3 loops often contact the MHC-I, and the germline-encoded CDR1 and -2 loops frequently participate in peptide-mediated interactions. Nevertheless, different TCRs adopt a roughly conserved docking mode over the pMHC-I, in which three MHC-I residues (65, 69, and 155) are invariably contacted by the TCR in one way or another. Nonetheless, the impact of mutations at these three positions, either individually or together, was not uniformly detrimental to TCR recognition of pHLA-B*0801 or pHLA-B*3508. Moreover, when TCR-pMHC-I recognition was impaired, this could be partially restored by expression of the CD8 coreceptor. The structure of a TCR-pMHC-I complex in which these three (65, 69, and 155) MHC-I positions were all mutated resulted in shifting of the TCR footprint relative to the cognate complex and formation of compensatory interactions. Collectively, our findings reveal the inherent adaptability of the TCR in maintaining peptide recognition while accommodating changes to the central docking site on the pMHC-I.MHC restriction | T cell recognition | structural immunology | immunogenetics D uring thymic selection αβ T cell receptors (TCRs) are selected for weak reactivity with one or more self-peptides in complex with self-MHC (major histocompatibility complex), resulting in mature T cells being restricted to recognize processed peptides only when they are presented by self-MHC molecules (1). The exquisite specificity of TCR-pMHC binding must address the highly polymorphic nature of the MHC and variable peptide cargo. The antigen-recognition site of the TCR is made up of six complementarity-determining regions (CDRs), three each from the α and β chains (2). Currently, it is postulated that the CDR1 and 2 loops underpin the specificity or "bias" toward the MHC, whereas the CDR3 loops recognize the diverse range of bound peptides (3-5). Recent studies support the view that the T cell repertoire is intrinsically biased toward the MHC through contacts mediated by conserved TCR Vα and Vβ residues (6). However, the factors governing MHC restriction, a central paradigm of antigen-specific T cell immunity, remain unclear.Presumably as a consequence of the polymorphic pMHC landscape, and the inherent diversity of the responding T cell repertoire, structural studies have shown that the TCR engages the pMHC-I and pMHC-II surfaces in a range of different docking modes (2). Nevertheless, conserved pairwise interactions between closely related Vβ8.2 + TCRs and pMHC-II molecules were identified, leading to the concept that there are defined interaction "motifs" or "codons" between the Vα and/or Vβ domains of a TCR and a given MHC allotype (3,(6)(7)(8). Central to the "int...

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“…12 Clinically, HLA-B*44:02 and B*44:03 alleles are known to represent a non-permissive transplantation scenario 13 and are associated with strong alloreactive T-cell responses and acute graft-versus-host disease. Furthermore, substitutions at position 156 were demonstrated to modify T-cell alloreactivity in vitro for HLA-A2 subtypes [14][15][16] and HLA-B35 17,18 while polymorphism at this position also appears to be responsible for acute graft-versus-host disease in HLA-C mismatched donor-recipient pairs. 19 Position 156 is known to be one of the most non-permissive transplantation mismatches.…”

Section: Introductionmentioning

confidence: 99%

Position 156 influences the peptide repertoire and tapasin dependency of human leukocyte antigen B*44 allotypes

Badrinath¹,

Saunders²,

Huyton³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundPolymorphic differences between donor and recipient human leukocyte antigen class I molecules can result in graft-versus-host disease due to distinct peptide presentation. As part of the peptide-loading complex, tapasin plays an important role in selecting peptides from the pool of potential ligands. Class I polymorphisms can significantly alter the tapasin-mediated interaction with the peptide-loading complex and although most class I allotypes are highly dependent upon tapasin, some are able to load peptides independently of tapasin. ). From these alleles, only the high tapasin-dependency of human leukocyte antigen B*44:02 has been reported. Design and MethodsWe investigated the influence of position 156 polymorphisms on both the requirement of tapasin for efficient surface expression of each allotype and their peptide features. Genes encoding human leukocyte antigen B*44 variants bearing all possible substitutions at position 156 were lentivirally transduced into human leukocyte antigen class I-negative LCL 721.221 cells and the tapasin-deficient cell line LCL 721.220. ResultsExclusively human leukocyte antigen B*44:28 156Arg was expressed on the surface of tapasin-deficient cells, suggesting that the remaining B*44/156 variants are highly tapasin-dependent. Our computational analysis suggests that the tapasin-independence of human leukocyte antigen B*44:28 156Arg is a result of stabilization of the peptide binding region and generation of a more peptide receptive state. Sequencing of peptides eluted from human leukocyte antigen B*44 molecules by liquid chromatography-electrospray ionization-mass spectrometry (LTQOrbitrap) demonstrated that both B*44:02 and B*44:28 share the same overall peptide motif and a certain percentage of their individual peptide repertoires in the presence and/or absence of tapasin. ConclusionsHere we report for the first time the influence of position 156 on the human leukocyte antigen/ tapasin association. Additionally, the results of peptide sequencing suggest that tapasin chaperoning is needed to acquire peptides of unusual length.Key words: HLA polymorphism, peptide-loading complex, tapasin, peptide-binding motif.Citation: Badrinath S, Saunders P, Huyton T, Aufderbeck S, Hiller O, Blasczyk R, and Bade-Doeding C. Position 156 influences the peptide repertoire and tapasin dependency of human leukocyte antigen B*44 allotypes. Haematologica 2012;97(1):98-106. doi:10.3324/haematol.2011

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The impact of HLA‐B micropolymorphism outside primary peptide anchor pockets on the CTL response to CMV

Cited by 44 publications

References 45 publications

Impact of clonal competition for peptide-MHC complexes on the CD8+ T-cell repertoire selection in a persistent viral infection

Impact of clonal competition for peptide-MHC complexes on the CD8+ T-cell repertoire selection in a persistent viral infection

Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability

Position 156 influences the peptide repertoire and tapasin dependency of human leukocyte antigen B*44 allotypes

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