T‐cell selection in the thymus: New routes toward the identification of the self‐peptide ligandome presented by thymic epithelial cells

Sousa, Laura; Rodrigues, Pedro M.; Alves, Nuno L.

doi:10.1002/eji.202250202

Cited by 4 publications

(4 citation statements)

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“…This includes the DPbla (blast) stage that occurs after the ISP stage and is characterized by rapid proliferation, the DPre (rearranging) stage in which the TCRα locus is rearranged and the mature TCR can receive signal for positive selection, and the DPsel (selection) stage when cells undergo positive selection ( 53 ). Positive selection is mediated by antigen presenting cells called cortical thymic epithelial cells (cTECs) that express self-MHC molecules for DP thymocytes to sample TCR binding for sufficient affinity to promote survival ( 54 , 55 ). Upon completion of positive selection, DP thymocytes downregulate either CD4 or CD8 to become CD4SP or CD8 single positive (CD8SP) and migrate to the thymic medulla.…”

Section: Introductionmentioning

confidence: 99%

“…Upon completion of positive selection, DP thymocytes downregulate either CD4 or CD8 to become CD4SP or CD8 single positive (CD8SP) and migrate to the thymic medulla. Negative selection then occurs through a process of affinity-based selection in which MHC:self-antigen on mTECs and thymic dendritic cells is presented to CD4SP and CD8SP cells, although evidence exists suggesting that some negative selection can also occur at the DP stage in the cortex or corticomedullary junction ( 55 – 57 ). Expression of self-antigen (aka TRAs) is driven by key transcription regulators such as Aire and Fezf2 ( 58 ).…”

Section: Introductionmentioning

confidence: 99%

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Transcriptomic profiling of thymic dysregulation and viral tropism after neonatal roseolovirus infection

Belean,

Xue,

Cisneros

et al. 2024

Front. Immunol.

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IntroductionHerpesviruses, including the roseoloviruses, have been linked to autoimmune disease. The ubiquitous and chronic nature of these infections have made it difficult to establish a causal relationship between acute infection and subsequent development of autoimmunity. We have shown that murine roseolovirus (MRV), which is highly related to human roseoloviruses, induces thymic atrophy and disruption of central tolerance after neonatal infection. Moreover, neonatal MRV infection results in development of autoimmunity in adult mice, long after resolution of acute infection. This suggests that MRV induces durable immune dysregulation.MethodsIn the current studies, we utilized single-cell RNA sequencing (scRNAseq) to study the tropism of MRV in the thymus and determine cellular processes in the thymus that were disrupted by neonatal MRV infection. We then utilized tropism data to establish a cell culture system.ResultsHerein, we describe how MRV alters the thymic transcriptome during acute neonatal infection. We found that MRV infection resulted in major shifts in inflammatory, differentiation and cell cycle pathways in the infected thymus. We also observed shifts in the relative number of specific cell populations. Moreover, utilizing expression of late viral transcripts as a proxy of viral replication, we identified the cellular tropism of MRV in the thymus. This approach demonstrated that double negative, double positive, and CD4 single positive thymocytes, as well as medullary thymic epithelial cells were infected by MRV in vivo. Finally, by applying pseudotime analysis to viral transcripts, which we refer to as “pseudokinetics,” we identified viral gene transcription patterns associated with specific cell types and infection status. We utilized this information to establish the first cell culture systems susceptible to MRV infection in vitro.ConclusionOur research provides the first complete picture of roseolovirus tropism in the thymus after neonatal infection. Additionally, we identified major transcriptomic alterations in cell populations in the thymus during acute neonatal MRV infection. These studies offer important insight into the early events that occur after neonatal MRV infection that disrupt central tolerance and promote autoimmune disease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transcriptomic profiling of thymic dysregulation and viral tropism after neonatal roseolovirus infection

Belean,

Xue,

Cisneros

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

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“…This includes the DPbla (blast) stage that occurs after the ISP stage and is characterized by rapid proliferation, the DPre (rearranging) stage in which the TCRa locus is rearranged and the mature TCR can receive signal for positive selection, and the DPsel (selection) stage when cells undergo positive selection (53). Positive selection is mediated by antigen presenting cells called cortical thymic epithelial cells (cTECs) that express self-MHC molecules for DP thymocytes to sample TCR binding for sufficient affinity to promote survival (54,55). Upon completion of positive selection, DP thymocytes downregulate either CD4 or CD8 to become CD4SP or CD8 single positive (CD8SP) and migrate to the thymic medulla.…”

Section: Introductionmentioning

confidence: 99%

“…Upon completion of positive selection, DP thymocytes downregulate either CD4 or CD8 to become CD4SP or CD8 single positive (CD8SP) and migrate to the thymic medulla. Negative selection then occurs through a process of affinity-based selection in which MHC:self-antigen on mTECs and thymic dendritic cells is presented to CD4SP and CD8SP cells, although evidence exists suggesting that some negative selection can also occur at the DP stage in the cortex or corticomedullary junction (55)(56)(57). Expression of self-antigen (aka TRAs) is driven by key transcription regulators such as Aire and Fezf2 (58).…”

Section: Introductionmentioning

confidence: 99%

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Determinants of tumor immune evasion: the role of T cell exposed motif frequency and mutant amino acid exposure

Homan

Bremel

2023

Front. Immunol.

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Few neoepitopes detected in tumor biopsies are immunogenic. Tumor-specific T cell responses require both the presentation of an epitope that differs from wildtype and the presence of T cells with neoepitope-cognate receptors. We show that mutations detected in tumor biopsies result in an increased frequency of rare amino acid combinations compared to the human proteome and gastrointestinal microorganisms. Mutations in a large data set of oncogene and tumor suppressor gene products were compared to wildtype, and to the count of corresponding amino acid motifs in the human proteome and gastrointestinal microbiome. Mutant amino acids in T cell exposed positions of potential neoepitopes consistently generated amino acid motifs that are less common in both proteome reference datasets. Approximately 10% of the mutant amino acid motifs are absent from the human proteome. Motif frequency does not change when mutants were positioned in the MHC anchor positions hidden from T cell receptors. Analysis of neoepitopes in GBM and LUSC cases showed less common T cell exposed motifs, and HLA binding preferentially placing mutant amino acids in an anchor position for both MHC I and MHC II. Cross-presentation of mutant exposed neoepitopes by MHC I and MHC II was particularly uncommon. Review of a tumor mutation dataset known to generate T cell responses showed immunogenic epitopes were those with mutant amino acids exposed to the T cell receptor and with exposed pentamer motifs present in the human and microbiome reference databases. The study illustrates a previously unrecognized mechanism of tumor immune evasion, as rare T cell exposed motifs produced by mutation are less likely to have cognate T cells in the T cell repertoire. The complex interactions of HLA genotype, binding positions, and mutation specific changes in T cell exposed motif underscore the necessity of evaluating potential neoepitopes in each individual patient.

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T‐cell selection in the thymus: New routes toward the identification of the self‐peptide ligandome presented by thymic epithelial cells

Cited by 4 publications

References 50 publications

Transcriptomic profiling of thymic dysregulation and viral tropism after neonatal roseolovirus infection

Transcriptomic profiling of thymic dysregulation and viral tropism after neonatal roseolovirus infection

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Determinants of tumor immune evasion: the role of T cell exposed motif frequency and mutant amino acid exposure

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