T Cells Compete for Access to Antigen-Bearing Antigen-Presenting Cells

Kedl, Ross M.; Rees, William; Hildeman, David A.; Schaefer, Brian C.; Mitchell, Tom; Kappler, John W.; Marrack, Philippa

doi:10.1084/jem.192.8.1105

Cited by 390 publications

(399 citation statements)

References 35 publications

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“…T-cell expansion during the virus challenge possibly due to CTL competition [29][30][31]. As we observed cross-priming of GP33 and NP396 with i-HEK-LyUV cells, one would expect to see a response dominated by GP33 and NP396 during a subsequent virus challenge.…”

Section: Discussionmentioning

confidence: 78%

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

et al. 2010

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The initiation of CD8 1 T cell (CTL) immune responses can occur via cross-priming. Recent data suggested a relationship between cross-presentation and immunodominance of epitope-specific T cells. To test this association, we evaluated the efficacy of crosspresentation for several virus epitopes in vitro and examined if this can be extrapolated in vivo. Employing lymphocytic choriomeningitis virus (LCMV), we demonstrate that the cross-presentation and cross-priming of LCMV antigens were dominated by NP396, but not NP205 when analyzing the LCMV-NP. Although with LCMV-GP, cross-presentation was dominated by GP276, and cross-priming was dominated by GP33. Importantly, although NP396 was significantly more efficient than GP33 in cross-presentation, cross-priming of their specific CTL was comparable. In a subsequent virus challenge after cross-priming, GP33-specific CTL dominated the response. Accordingly, based on our data, the ability of viral epitopes to be cross-presented in vitro does not entirely reflect what would occur in cross-priming. Thus, weak cross-presenting antigens may still cross-prime an efficient CTL response depending on other in vivo elements such as the naïve T-cell precursor frequencies.

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Section: Discussionmentioning

confidence: 78%

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

et al. 2010

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“…58 , 59 In our model, both peptides were modified to increase the affinity for class I MHC-binding. 60 , 61 Therefore, since Melan-A and gp100 were injected at the same site, a local Ag-dependent cross competition of T cells with different specificities could have occurred.…”

Section: Discussionmentioning

confidence: 99%

Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients

et al. 2018

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We have recently described that DNA-damage inducing drug DTIC, administered before peptide (Melan-A and gp100)-vaccination, improves anti-tumor CD8+ Melan-A-specific T-cell functionality, enlarges the Melan-A+ TCR repertoire and impacts the overall survival of melanoma patients. To identify whether the two Ags employed in the vaccination differently shape the anti-tumor response, herein we have carried out a detailed analysis of phenotype, anti-tumor functionality and TCR repertoire in treatment-driven gp100-specific CD8+ T cells, in the same patients previously analyzed for Melan-A. We found that T-cell clones isolated from patients treated with vaccination alone possessed an Early/intermediate differentiated phenotype, whereas T cells isolated after DTIC plus vaccination were late-differentiated. Sequencing analysis of the TCRBV chains of 29 treatment-driven gp100-specific CD8+ T-cell clones revealed an oligoclonal TCR repertoire irrespective of the treatment schedule. The high anti-tumor activity observed in T cells isolated after chemo-immunotherapy was associated with low PD-1 expression. Differently, T-cell clones isolated after peptide-vaccination alone expressed a high level of PD-1, along with LAG-3 and TIM-3, and were neither tumor-reactive nor polyfunctional. Blockade of PD-1 reversed gp100-specific CD8+ T-cell dysfunctionality, confirming the direct role of this co-inhibitory molecule in suppressing anti-tumor activity, differently from what we have previously observed for Melan-A+CD8+ T cells, expressing PD-1 but highly functional. These findings indicate that the functional advantage induced by combined chemo-immunotherapy is determined by the tumor antigen nature, T-cell immune-checkpoints phenotype, TCR repertoire diversity and anti-tumor T-cell quality and highlights the importance of integrating these parameters to develop effective immunotherapeutic strategies.

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“…Furthermore, T cells that require N-terminal residues for activation appear to be inhibitory for those T cells less dependent on such flanking residues, possibly through a competitive mechanism for antigen-MHC binding [34], or by secreting regulatory cytokines (Enomoto et al, unpublished data). In summary, different T cell repertoires specific for a dominant determinant region of a self antigen (such as GAD65 p524-543) can be induced to function diversely as a consequence of antigen processing.…”

Section: Discussionmentioning

confidence: 99%

“…In the NOD background, the antigen processing machinery removes N-terminal residues, thus limiting its T cell repertoire. It is possible, alternatively, that endogenously primed NOD T cells might be unusually responsive to peptide-MHC complexes, or in the NOR, the unprimed p524-543 reactive T cells require N-terminal flanking regions for complete activation.Furthermore, T cells that require N-terminal residues for activation appear to be inhibitory for those T cells less dependent on such flanking residues, possibly through a competitive mechanism for antigen-MHC binding [34], or by secreting regulatory cytokines (Enomoto et al, unpublished data). In summary, different T cell repertoires specific for a dominant determinant region of a self antigen (such as GAD65 p524-543) can be induced to function diversely as a consequence of antigen processing.…”

mentioning

confidence: 99%

N‐terminal flanking residues of a diabetes‐associated GAD65 determinant are necessary for activation of antigen‐specific T cells in diabetes‐resistant mice

Dai¹,

Jensen²,

Marrero³

et al. 2008

Eur J Immunol

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A diabetes-associated peptide in the glutamic acid decarboxylase 65 (GAD65) molecule, p524-543, activates two distinct populations of T cells, which apparently play opposite roles in the development of diabetes in NOD mice. By comparing the fine specificity of these two T cell repertoires using a nested set of truncated peptides that cover the p524-543 region, we found, surprisingly, that all clones recognized the same core within this peptide, p530-539. The core itself was non-immunogenic, but the residues flanking this shared sequence played the crucial role in selecting T cells to activate. A peptide missing N-terminal flanking residues at position 528 and 529 was stimulatory in NOD but not in MHC-matched, NODresistant (NOR) mice, suggesting that a protective response in the resistant mice may require T cell recognition of one or more of the N-terminal flanking residues. T cell repertoire studies demonstrated selective clonal expansions within the BV4 TCR family that dominates the p524-543 response in NOD but not in NOR mice. These data suggest that processing or trimming events affecting T cell recognition of very few flanking residues of diabetes-associated determinants might be involved in the protective response in NOR mice.Key words: Antigens/peptides/epitopes Á Autoimmune Á GAD65 Á T cell repertoire IntroductionProcessing and presentation of islet antigens on I-A g7 molecules is a crucial aspect in the emergence of spontaneous type 1 diabetes (T1D) in NOD mice. How the peptide-binding motif of I-A g7 relates to the selection and processing of peptide determinants and subsequent repertoire choice in this mouse strain and its related strains remains unresolved. Several autoantigens have been defined in type 1 diabetes (T1D) using antigen-specific antibody and/or T cell assays, including glutamic acid decarboxylase 65 (GAD65), proinsulin and insulin, insulinoma-like antigen 2 (IA-2), and insulin-specific glucose-6-phosphatase catalytic subunitrelated protein (IGRP). In NOD mice, several peptides from these autoantigens have been identified as targets of T cell responses. These include GAD65 p524-543 and p246-266 [1, 2], GAD65 p206-220 and p286-300 [3], insulin B chain p9-23 [4,5], proinsulin p24-33 (proinsulin II p48-57) [6],, and insulin-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) p206-214 [8]. Extensive analysis of TCR BV gene usage and CDR3 sequences have demonstrated that the early islet-infiltrating T cell clonal expansion is restricted to distinct BV families, e.g., BV4 [9], BV2, BV12, BV14 [10], BV13 [11], BV8.2 [12], and BV1 [13]. This indicates that selective clonal expansion of antigen-specific T cells is one characteristic of the initial inflammatory response in the islets. A recombinant congenic strain, which is NOD-resistant (NOR) and derives *88% of its genome from the NOD strain, including the I-A g7 MHC haplotype, was produced adventitiously at the Jackson Laboratory [14], and can be used as a control strain, since NOR mice are insulitis resistant and diabetes ...

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T Cells Compete for Access to Antigen-Bearing Antigen-Presenting Cells

Cited by 390 publications

References 35 publications

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients

N‐terminal flanking residues of a diabetes‐associated GAD65 determinant are necessary for activation of antigen‐specific T cells in diabetes‐resistant mice

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