Thymocyte Maturation: Selection for In-Frame TCR α-Chain Rearrangement Is Followed by Selection for Shorter TCR β-Chain Complementarity-Determining Region 3

Yassai, Maryam; Gorski, Jack

doi:10.4049/jimmunol.165.7.3706

Cited by 35 publications

(38 citation statements)

References 34 publications

(35 reference statements)

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“…Notably, the naive repertoires were slightly skewed toward shorter D b lengths and contained a higher fraction of TCRb sequences with either 0 or 1 nucleotide addition. These observations are consistent with previous reports showing a slight shortening of CDR3 lengths during the transition from the DP stage to the CD4 + or CD8 + single positive (SP) stage (17,(22)(23)(24). Such selection events might exert a minor effect on the sharing of TCRs between individuals.…”

Section: Comparison Of Naive and Cd4 + Cd8 + Tcrb Repertoiressupporting

confidence: 93%

Recombinatorial Biases and Convergent Recombination Determine Interindividual TCRβ Sharing in Murine Thymocytes

et al. 2012

The Journal of Immunology

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Overlap of TCR repertoires among individuals provides the molecular basis for public T cell responses. By deep-sequencing the TCRβ repertoires of CD4+CD8+ thymocytes from three individual mice, we observed that a substantial degree of TCRβ overlap, comprising ∼10–15% of all unique amino acid sequences and ∼5–10% of all unique nucleotide sequences across any two individuals, is already present at this early stage of T cell development. The majority of TCRβ sharing between individual thymocyte repertoires could be attributed to the process of convergent recombination, with additional contributions likely arising from recombinatorial biases; the role of selection during intrathymic development was negligible. These results indicate that the process of TCR gene recombination is the major determinant of clonotype sharing between individuals.

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Section: Comparison Of Naive and Cd4 + Cd8 + Tcrb Repertoiressupporting

confidence: 93%

Recombinatorial Biases and Convergent Recombination Determine Interindividual TCRβ Sharing in Murine Thymocytes

et al. 2012

The Journal of Immunology

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“…The implications for TCRBV CDR3 length in Ag-specific immune response have not yet been completely elucidated, although it has been suggested to be dependent on thymic maturation, with positive selection being associated with shorter sequences and longer CDR3 with a higher affinity interaction with the peptide-MHC. 43 …”

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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“…Thymocytes were enriched for CD8 SP by magnetic bead removal of CD4-positive thymocytes (CD4 SP and most DP cells). The CD8-enriched fraction was stained with mAb for CD4, CD8, and CD3, and the CD8 SP fraction collected as described (11). Only thymi showing normal CD4 and CD8 profiles were used for sorting.…”

Section: Preparation Of Cd8 Sp Thymocytesmentioning

confidence: 99%

“…DNA was prepared from sorted CD8 SP and amplified with BV19-J2.7 primers as described (11). The product was fractionated on denaturing polyacrylamide urea gels and the 150-bp band corresponding to the expected size of CDR3 for an M1 58-66 -specific clonotype was cut from the gel.…”

Section: Bv19-j27 Clonotype Analysismentioning

confidence: 99%

Naive T Cell Repertoire Skewing in HLA-A2 Individuals by a Specialized Rearrangement Mechanism Results in Public Memory Clonotypes

Yassai

Bosenko

Unruh

et al. 2011

The Journal of Immunology

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How the naive T cell repertoire arises and forms the memory repertoire is still poorly understood. This relationship was analyzed by taking advantage of the focused TCR usage in HLA-A2–restricted CD8 memory T cell responses to influenza M158–66. We analyzed rearranged BV19 genes from CD8 single-positive thymocytes, a surrogate for the naive repertoire, from 10 HLA-A2 individuals. CDR3 amino acid sequences associated with response to influenza were observed at higher frequencies than expected by chance, an indicator of preselection. We propose that a rearrangement mechanism involving long P-nucleotide addition from the J2.7 region explains part of this increase. Special rearrangement mechanisms can result in identical T cells in different individuals, referred to as public responses. Indeed, the rearrangements utilizing long P nucleotide additions were commonly observed in the response to the M158–66 epitope in 30 HLA-A2 middle-aged adults. Thus, in addition to negative and positive selection, special rearrangement mechanisms may influence the composition of the naive repertoire, resulting in more robust responses to a pathogen in some individuals.

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Thymocyte Maturation: Selection for In-Frame TCR α-Chain Rearrangement Is Followed by Selection for Shorter TCR β-Chain Complementarity-Determining Region 3

Cited by 35 publications

References 34 publications

Recombinatorial Biases and Convergent Recombination Determine Interindividual TCRβ Sharing in Murine Thymocytes

Recombinatorial Biases and Convergent Recombination Determine Interindividual TCRβ Sharing in Murine Thymocytes

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

Naive T Cell Repertoire Skewing in HLA-A2 Individuals by a Specialized Rearrangement Mechanism Results in Public Memory Clonotypes

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