Thymic expression of peripheral tissue antigens in humans: a remarkable variability among individuals

Takase, Hiroshi; Yu, Cheng‐Rong; Mahdi, Rashid M.; Douek, Daniel C.; DiRusso, Gregory B.; Midgley, Frank M.; Dogra, Rajpreet; Allende, Gloria; Rosenkranz, Eliot R.; Pugliese, Alberto; Egwuagu, Charles E.; Gery, Igal

doi:10.1093/intimm/dxh275

Cited by 53 publications

(40 citation statements)

References 36 publications

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Section: Discussionmentioning

confidence: 91%

“…These findings may also help to explain why CD8 1 T cells recognizing those peptides, which derive from selfproteins, are not deleted in the thymus by negative selection. Ectopic expression of tissue-specific antigens was, indeed, observed in the thymus, which also contains high amounts of IP [15][16][17].The comparative analysis of the digests indicates that the production of a given spliced peptide is directly linked to the production of the splicing partner fragments. These findings support the transpeptidation model proposed for the splicing reaction and demonstrate that splicing is not intrinsically favored by specific structural features of a given proteasome type, but is directly dependent on the amount of each peptidic partner produced.…”

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confidence: 91%

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Differences in the production of spliced antigenic peptides by the standard proteasome and the immunoproteasome

Dalet¹,

Stroobant²,

Vigneron³

et al. 2010

Eur J Immunol

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Peptide splicing allows the production of antigenic peptides composed of two fragments initially non-contiguous in the parental protein. The proposed mechanism of splicing is a transpeptidation occurring within the proteasome. Three spliced peptides, derived from FGF-5, melanoma protein gp100 and nuclear protein SP110, have been described. Here, we compared the production of these spliced peptides by the standard proteasome and the immunoproteasome. Differential isotope labelling was used to quantify (by mass spectrometry) the fragments contained in digests obtained with precursor peptides and purified proteasomes. The results show that both the standard and the immunoproteasomes can produce spliced peptides although they differ in their efficiency of production of each peptide. The FGF-5 and gp100 peptides are more efficiently produced by the standard proteasome, whereas the SP110 peptide is more efficiently produced by the immunoproteasome. This seems to result from differences in the production of the two splicing partners, which depends on a balance between cleavages liberating or destroying those fragments. By showing that splicing depends on the efficiency of production of the splicing partners, these results also support the transpeptidation model of peptide splicing. Furthermore, given the presence of immunoproteasomes in dendritic cells and cells exposed to IFN-c, the findings may be relevant for vaccine design.Key words: Mass Spectrometry . Peptide splicing . Proteasome IntroductionSpliced peptides comprise two non-contiguous fragments of the parental protein that are linked together after the excision of an intervening segment. Three spliced antigenic peptides have been described to date. The first is a 9-mer (NTYASPRFK) derived from FGF-5 and presented by HLA-A3 molecules [1]. It was identified using CTL raised against a human renal carcinoma. Another spliced peptide (RTKQLYPEW) is produced from the melanosomal protein gp100 and is recognized, in association with HLA-A32, by CTL raised against a human melanoma [2]. The third example of spliced peptide (SLPRGTSTPK) is a human minor histocompatibility antigen created by a polymorphism in the SP110 gene [3]. This peptide is recognized, in association with HLA-A3, by CTL isolated from a myeloma patient after MHCmatched hematopoietic cell transplantation.We previously showed that the three spliced peptides were produced by transpeptidation inside the catalytic chamber of the proteasome [2][3][4]. In the course of proteolysis, the hydroxyl group of the N-terminal threonine of a catalytic b-subunit produces a nucleophilic attack on the peptide bond, leading to the formation of an acyl-enzyme intermediate between the SHORT COMMUNICATIONCorrespondence: Dr. Benoît J. Van In this study, we compared the production of the three spliced antigenic peptides by the standard proteasome (SP) and its IFN-ginducible counterpart, the immunoproteasome (IP), using a cellular approach and an in vitro approach. We used differential isotope labelling to perform a direct and ...

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Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 91%

Differences in the production of spliced antigenic peptides by the standard proteasome and the immunoproteasome

Dalet¹,

Stroobant²,

Vigneron³

et al. 2010

Eur J Immunol

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“…In this regard, MelA and PGT peptides, which are both derived from self-proteins, are recognized at much higher frequencies than the other immunodominant peptides herein studied, which were all derived from foreign organisms. Along this line, thymic expression of mRNA encoding for MelanA has been previously reported [25,26], although this mRNA might be in most cases truncated, precluding expression of the MelA peptide [27]. The preferential selection of the corresponding Ag-specific T-cell subsets in A2 + donors might thus result from TCR engagement by relevant or closely related p-A2 complexes expressed at densities low enough in the thymus to avoid T-cell deletion [28,29].…”

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confidence: 97%

Role of the MHC restriction during maturation of antigen‐specific human T cells in the thymus

et al. 2015

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In the thymus, a T-cell repertoire able to confer protection against infectious and noninfectious agents in a peptide-dependent, self-MHC-restricted manner is selected. Direct detection of Ag-specific thymocytes, and analysis of the impact of the expression of the MHCrestricting allele on their frequency or function has never been studied in humans because of the extremely low precursor frequency. Here, we used a tetramer-based enrichment protocol to analyze the ex vivo frequency and activation-phenotype of human thymocytes specific for self, viral and tumor-antigens presented by HLA-A*0201 (A2) in individuals expressing or not this allele. Ag-specific thymocytes were quantified within both CD4CD8 double or single-positive compartments in every donor. Our data indicate that the maturation efficiency of Ag-specific thymocytes is poorly affected by HLA-A2 expression, in terms of frequencies. Nevertheless, A2-restricted T-cell lines from A2 + donors reacted to A2 + cell lines in a highly peptide-specific fashion, whereas their alloreactive counterparts showed off-target activity. This first ex vivo analysis of human antigen-specific thymocytes at different stages of human T-cell development should open new perspectives in the understanding of the human thymic selection process. Keywords: Antigen r Human T cells r MHC r Tetramers r Thymocytes See accompanying Commentary by Ciucci and BosselutAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe thymus generates a highly diverse T-cell repertoire able to recognize virtually any antigen that could be encountered by a given individual along his/her life. This diversity is achieved through two main mechanisms. First by the acquisition by CD4 + CD8 + double-positive (DP) thymocytes of a clonally distributed T cell receptor (TCR) that is generated after somatic recombination of TCR V(D)J gene segments and nontemplated nucleotide Correspondence: Dr. Xavier Saulquin e-mail: xavier.saulquin@univ-nantes.fradditions. This quasi-random mechanism allows for the generation of up to 10 15 different receptors [1]. Second, by the shaping of this initial T-cell repertoire by positive and negative thymic selection processes that will favor emergence of a self major histocompatibility molecules (MHC)-restricted, yet self-tolerant, TCR repertoire carried by mature naïve single-positive (SP) T cells. As a consequence of this maturation process, the diversity of SP αβ T cells in a given individual falls in the range of 10 6 to 10 8 [2]. * LH and FL equally contributed to this work. The respective contributions of positive and negative thymic selection processes to the generation of a mature T-cell repertoire possibly biased towards recognition of peptides restricted by host MHC alleles are still debated. Indeed, this phenomenon referred to as "host or Self-MHC-restriction" is a consequence of a balance between (i) the need for a thymocyte to get survival signals from TCR upon interactions of weak/intermediate avidi...

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“…A large number of self-antigens are expressed at highly variable levels in the thymic epithelium. 92 Given the quantitative nature of the thymic selection processes, 93 a general reduction in the expression of the disease-associated class II alleles in the thymus could result in loss of central tolerance in which thymocytes with excessive reactivity to self-antigens escape elimination.…”

Section: Hla-drb9 Dr8mentioning

confidence: 99%

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

et al. 2009

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Major histocompatibility complex (MHC) class II molecules are central to adaptive immune responses and maintenance of selftolerance. Since the early 1970s, the MHC class II region at chromosome 6p21 has been shown to be associated with a remarkable number of autoimmune, inflammatory and infectious diseases. Given that a full explanation for most MHC class II disease associations has not been reached through analysis of structural variation alone, in this review we examine the role of genetic variation in modulating gene expression. We describe the intricate architecture of the MHC class II regulatory system, indicating how its unique characteristics may relate to observed associations with disease. There is evidence that haplotypespecific variation involving proximal promoter sequences can alter the level of gene expression, potentially modifying the emergence and expression of key phenotypic traits. Although much emphasis has been placed on cis-regulatory elements, we also examine the role of more distant enhancer elements together with the evidence of dynamic inter-and intra-chromosomal interactions and epigenetic processes. The role of genetic variation in such mechanisms may hold profound implications for susceptibility to common disease.

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Thymic expression of peripheral tissue antigens in humans: a remarkable variability among individuals

Cited by 53 publications

References 36 publications

Differences in the production of spliced antigenic peptides by the standard proteasome and the immunoproteasome

Differences in the production of spliced antigenic peptides by the standard proteasome and the immunoproteasome

Role of the MHC restriction during maturation of antigen‐specific human T cells in the thymus

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

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