CD8+ TCR Repertoire Formation Is Guided Primarily by the Peptide Component of the Antigenic Complex

Koning, Dan; Costa, Ana I.; Hoof, Ilka; Miles, John J.; Nanlohy, Nening M.; Ladell, Kristin; Matthews, Katherine; Venturi, Vanessa; Schellens, Ingrid M. M.; Borghans, José A. M.; Keşmir, Can; Price, David A.; Baarle, Debbie van

doi:10.4049/jimmunol.1202466

Cited by 37 publications

(30 citation statements)

References 59 publications

(70 reference statements)

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“…Moreover, the extent of TCR sharing varied as a function of epitope specificity. In line with previous studies, clonal diversity per se did not correlate with immunodominance (73). However, the most frequently targeted epitopes mobilized cognate repertoires characterized by the presence of high frequency public TCRs.…”

Section: Discussionsupporting

confidence: 92%

CD8+ TCR Bias and Immunodominance in HIV-1 Infection

Kløverpris

McGregor

McLaren

et al. 2015

The Journal of Immunology

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Immunodominance describes a phenomenon whereby the immune system consistently targets only a fraction of the available antigen pool derived from a given pathogen. In the case of CD8+ T-cells, these constrained epitope targeting patterns are linked to human leukocyte antigen (HLA) class-I expression and determine disease progression. Despite the biological importance of these predetermined response hierarchies, however, little is known about the factors that control immunodominance in vivo. In this study, we conducted an extensive analysis of CD8+ T-cell responses restricted by a single HLA class-I molecule to evaluate the mechanisms that contribute to epitope targeting frequency and antiviral efficacy in HIV-1 infection. A clear immunodominance hierarchy was observed across 20 different epitopes restricted by HLA-B*42:01, which is highly prevalent in populations of African origin. Moreover, in line with previous studies, Gag-specific responses and targeting breadth were associated with lower viral load set-points. However, peptide-HLA-B*42:01 binding affinity and stability were not significantly linked with targeting frequencies. Instead, immunodominance correlated with epitope-specific usage of public TCRs, defined as amino acid residue-identical TRB sequences that occur in multiple individuals. Collectively, these results provide the first insights into a potential link between shared TCR recruitment, immunodominance and antiviral efficacy in a major human infection.

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Section: Discussionsupporting

confidence: 92%

CD8+ TCR Bias and Immunodominance in HIV-1 Infection

Kløverpris

McGregor

McLaren

et al. 2015

The Journal of Immunology

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“…S4H). For one of these TCRs we were able to predict the putative antigen as EBNA-3, an Epstein-Barr virus protein based on prior TCR repertoire analyses (26). The presence of shared, relatively prominent clones, in combination with our RNA-seq data, support the possibility of an adaptive immune response in a subset of DCIS and a potential decline of this after progression to IDC.…”

Section: Resultsmentioning

confidence: 99%

Immune Escape in Breast Cancer DuringIn Situto Invasive Carcinoma Transition

et al. 2017

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To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB+CD8+ T cells in IDC than in DCIS, including in matched DCIS recurrent IDC. TCR clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT expressing T cells were more frequent in DCIS whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple negative IDCs. Co-amplification of 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes. Our results show co-evolution of cancer cells and the immune microenvironment during tumor progression.

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“…The shaded area (orange) indicates the mean ± SD calculated for pairs formed by twin with each unrelated individual. we can suggest that these clonotypes recognize the same CMV peptide (as they have identical CDR3) but presented by another MHC molecule (as they have different V segments coding for the CDR1/CDR2 that recognize MHC) (28). No such observation was made for the α chain where identical/ different V segments among matched CMV-positive CDR3s are distributed quite randomly between individuals.…”

Section: Shared Clonotypes Features Are Different For Twins and Unrelmentioning

confidence: 88%

Distinctive properties of identical twins' TCR repertoires revealed by high-throughput sequencing

Zvyagin

Pogorelyy

Ivanova

et al. 2014

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

117

149

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Adaptive immunity in humans is provided by hypervariable Ig-like molecules on the surface of B and T cells. The final set of these molecules in each organism is formed under the influence of two forces: individual genetic traits and the environment, which includes the diverse spectra of alien and self-antigens. Here we assess the impact of individual genetic factors on the formation of the adaptive immunity by analyzing the T-cell receptor (TCR) repertoires of three pairs of monozygous twins by next-generation sequencing. Surprisingly, we found that an overlap between the TCR repertoires of monozygous twins is similar to an overlap between the TCR repertoires of nonrelated individuals. However, the number of identical complementary determining region 3 sequences in two individuals is significantly increased for twin pairs in the fraction of highly abundant TCR molecules, which is enriched by the antigen-experienced T cells. We found that the initial recruitment of particular TCR V genes for recombination and subsequent selection in the thymus is strictly determined by individual genetic factors. J genes of TCRs are selected randomly for recombination; however, the subsequent selection in the thymus gives preference to some α but not β J segments. These findings provide a deeper insight into the mechanism of TCR repertoire generation.immunogenetics | TCR repertoire analysis | twin studies

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CD8+ TCR Repertoire Formation Is Guided Primarily by the Peptide Component of the Antigenic Complex

Cited by 37 publications

References 59 publications

CD8+ TCR Bias and Immunodominance in HIV-1 Infection

CD8+ TCR Bias and Immunodominance in HIV-1 Infection

Immune Escape in Breast Cancer DuringIn Situto Invasive Carcinoma Transition

Distinctive properties of identical twins' TCR repertoires revealed by high-throughput sequencing

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