Overlap and Effective Size of the Human CD8
            <sup>+</sup>
            T Cell Receptor Repertoire

Robins, Harlan; Srivastava, Santosh K.; Campregher, Paulo Vidal; Turtle, Cameron J.; Andriesen, Jessica; Riddell, Stanley R.; Carlson, Christopher S.; Warren, Edus H.

doi:10.1126/scitranslmed.3001442

Cited by 368 publications

(441 citation statements)

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“…The available data suggest that convergent recombination [37][38][39][40] and biases during recombination [33,37,41] are the major contributors of TCR sharing in TCR repertoires among individuals. Convergent recombination is the process whereby multiple recombination events 'converge' to produce the same nucleotide sequence and multiple nucleotide sequences "converge" to encode the same amino-acid sequence (Figure 1), which results in different TCR sequences to be generated with differential frequencies during recombination [37][38][39][40].…”

Section: How Does Initial V(d)j Recombination Determine Tcr Sharing?mentioning

confidence: 99%

“…Convergent recombination is the process whereby multiple recombination events 'converge' to produce the same nucleotide sequence and multiple nucleotide sequences "converge" to encode the same amino-acid sequence (Figure 1), which results in different TCR sequences to be generated with differential frequencies during recombination [37][38][39][40]. Recombinatorial biases include biased V/D/J gene usage and combination, bias in the number of nucleotide deletions at the coding ends of V/D/J gene segments, bias in the number of nucleotide additions and bias in base usage at the V-D/ D-J junctions [33,37,[41][42][43]. How those two determinants generate the substantial sharing of TCRs among individuals during initial recombination is discussed below.…”

Section: How Does Initial V(d)j Recombination Determine Tcr Sharing?mentioning

confidence: 99%

“…Detailed analyses on recombinatorial biases were facilitated by recent high-throughput sequencings [33,[49][50][51][52] (and our unpublished data), which enable comparison between the empirical TCR β repertoires and the simu- npg lated model being made, so that biases during recombination could be revealed. A simulated TCR β repertoire should incorporate the effect of random convergent recombination, which assumes random nucleotide deletion at the coding ends of those germline segments, and random nucleotide addition at the junctions within different V β -J β combination.…”

Section: Recombinatorial Biasesmentioning

confidence: 99%

“…Indeed, a large degree of overlap has been observed between the naïve TCR repertoires in inbred mice [31,32] and humans [33,34]. This phenomenon of TCR sharing within the naïve T-cell pool of multiple individuals provides the molecular basis for public T cell responses, enabling epitope-specific clonotype selection based on optimal TCR recognition operating on a partially common platform [35][36][37].…”

Section: Introductionmentioning

confidence: 99%

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Determinants of public T cell responses

et al. 2012

Cell Res

112

107

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Historically, sharing T cell receptors (TCRs) between individuals has been speculated to be impossible, considering the dramatic discrepancy between the potential enormity of the TCR repertoire and the limited number of T cells generated in each individual. However, public T cell response, in which multiple individuals share identical TCRs in responding to a same antigenic epitope, has been extensively observed in a variety of immune responses across many species. Public T cell responses enable individuals within a population to generate similar antigen-specific TCRs against certain ubiquitous pathogens, leading to favorable biological outcomes. However, the relatively concentrated feature of TCR repertoire may limit T cell response in a population to some other pathogens. It could be a great benefit for human health if public T cell responses can be manipulated. Therefore, the mechanistic insight of public TCR generation is important to know. Recently, high-throughput DNA sequencing has revolutionized the study of immune receptor repertoires, which allows a much better understanding of the factors that determine the overlap of TCR repertoire among individuals. Here, we summarize the current knowledge on public T-cell response and discuss future challenges in this field.

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Section: How Does Initial V(d)j Recombination Determine Tcr Sharing?mentioning

confidence: 99%

Section: How Does Initial V(d)j Recombination Determine Tcr Sharing?mentioning

confidence: 99%

Section: Recombinatorial Biasesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Determinants of public T cell responses

et al. 2012

Cell Res

112

107

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“…In this line, an interesting study recently proposed a numerical model of mouse TCR Va/Ja gene accessibility that pointed out unbalanced V-J associations resulting from preferential access to gene rearrangements [6]. Despite studies using high-throughput sequencing of TCR b chains [2,[7][8][9], a global view on the distribution of V-J rearrangement combinations of the TCR b chain in humans was lacking. Here, we have reanalyzed T-cell repertoire data that we generated in humanized NOD.SCID.gc À/À (NSG) mice [5] with the aim to determine the extent of the overlap between the T-cell repertoire of humans and humanized mice at the level of V-J rearrangements.…”

Section: Introductionmentioning

confidence: 99%

Half of the T‐cell repertoire combinatorial diversity is genetically determined in humans and humanized mice

Pham

Manuel²,

Petit

et al. 2011

Eur J Immunol

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In humanized mice, the T-cell repertoire is derived from genetically identical human progenitors in distinct animals. Thus, careful comparison of the T-cell repertoires of humanized mice with those of humans may reveal the contribution of genetic determinism on T-cell repertoire formation. Here, we performed a comprehensive assessment of the distribution of V-J combinations of the human b chain of the T-cell receptor (hTRBV) in NOD.SCID.cc À/À (NSG) humanized mice. We observed that numerous V-J combinations were equally distributed in the thymus and in the periphery of humanized mice compared with human references. A global analysis of the data, comparing repertoire perturbation indices in humanized NSG mice and unrelated human PBMCs, reveals that 50% of the hTRBV families significantly overlapped. Using multivariate ranking and bootstrap analyses, we found that 18% of all possible V-J combinations contributed close to 50% of the expressed diversity, with significant over-representation of BV5-J1.111.2 and BV6-J1.111.2 rearrangements. Finally, comparison of CD3 À and CD3 1 thymocyte repertoires indicated that the observed V-J combination overlap was already present before TCR-MHC selection in the thymus. Altogether, our results show that half of the T-cell repertoire combinatorial diversity in humans is genetically determined.Key words: Humanized mice . ISEApeaks . Multivariate score . T-cell repertoire . V-J rearrangements Supporting Information available online Introduction T-cell repertoire diversity is based upon tightly ordered genetic rearrangements of the T-cell receptor V, D and J genes. The available numbers of these genes in the genome constitutes a first level of diversity: to date, 33 and 65 genes encoding variable elements of the human T-cell receptor b chain (hTRBV) from 30 hTRBV families have been characterized in mice and humans respectively (according to the ImMunoGeneTics (IMGT) database (http://www.imgt.org)). An additional level of diversity comes from the association of single V, (D) and J elements together. The major determinant of repertoire diversity is then random addition of nucleotides at the junction of these V(D)J gene segments, constituting the CDR3 of the TCR. Finally, a fourth level of complexity originates from the association of the rearranged a and b chains of the TCR. In theory, these sequential processes occurring during T-cell differentiation in the thymus could Eur. J. Immunol. 2012. 42: 760-770 760 generate up to 10 15 different TCRs, a number far in excess of the number of T-cells in the body. The 'real' size of the repertoire is probably much lower though, with recent estimations of unique TCR b chains ranging from 10 6 to 4.10 6 in humans [1,2]. Mice reconstituted with a human immune system generated from hematopoietic precursors represent a new animal model for human immunology studies. The extent of the human T-cell repertoire diversity generated in mice may represent an important functional indicator [3], useful for immunological studies in the models. However, a...

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Toll-Like Receptor 4 Agonist Injection With Concurrent Radiotherapy in Patients With Metastatic Soft Tissue Sarcoma

Seo,

Lu,

Black

et al. 2023

JAMA Oncol

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ImportanceMetastatic soft tissue sarcomas (STSs) have limited systemic therapy options, and immunomodulation has not yet meaningfully improved outcomes. Intratumoral (IT) injection of the toll-like receptor 4 (TLR4) agonist glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE) has been studied as immunotherapy in other contexts.ObjectiveTo evaluate the safety, efficacy, and immunomodulatory effects of IT GLA-SE with concurrent radiotherapy in patients with metastatic STS with injectable lesions.Design, Setting, and ParticipantsThis phase 1 nonrandomized controlled trial of patients with STS was performed at a single academic sarcoma specialty center from November 17, 2014, to March 16, 2016. Data analysis was performed from August 2016 to September 2022.InterventionsTwo doses of IT GLA-SE (5 μg and 10 μg for 8 weekly doses) were tested for safety in combination with concurrent radiotherapy of the injected lesion.Main Outcomes and MeasuresPrimary end points were safety and tolerability. Secondary and exploratory end points included local response rates as well as measurement of antitumor immunity with immunohistochemistry and T-cell receptor (TCR) sequencing of tumor-infiltrating and circulating lymphocytes.ResultsTwelve patients (median [range] age, 65 [34-78] years; 8 [67%] female) were treated across the 2 dose cohorts. Intratumoral GLA-SE was well tolerated, with only 1 patient (8%) experiencing a grade 2 adverse event. All patients achieved local control of the injected lesion after 8 doses, with 1 patient having complete regression (mean regression, −25%; range, −100% to 4%). In patients with durable local response, there were detectable increases in tumor-infiltrating lymphocytes. In 1 patient (target lesion −39% at 259 days of follow-up), TCR sequencing revealed expansion of preexisting and de novo clonotypes, with convergence of numerous rearrangements coding for the same binding sequence (suggestive of clonal convergence to antitumor targets). Single-cell sequencing identified these same expanded TCR clones in peripheral blood after treatment; these T cells had markedly enhanced Tbet expression, suggesting TH1 phenotype.Conclusions and RelevanceIn this nonrandomized controlled trial, IT GLA-SE with concurrent radiotherapy was well tolerated and provided more durable local control than radiotherapy alone. Patients with durable local response demonstrated enhanced IT T-cell clonal expansion, with matched expansion of these clonotypes in the circulation. Additional studies evaluating synergism of IT GLA-SE and radiotherapy with systemic immune modulation are warranted.Trial RegistrationClinicalTrials.gov Identifier: NCT02180698

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Overlap and Effective Size of the Human CD8 ⁺ T Cell Receptor Repertoire

Cited by 368 publications

References 15 publications

Determinants of public T cell responses

Determinants of public T cell responses

Half of the T‐cell repertoire combinatorial diversity is genetically determined in humans and humanized mice

Toll-Like Receptor 4 Agonist Injection With Concurrent Radiotherapy in Patients With Metastatic Soft Tissue Sarcoma

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Overlap and Effective Size of the Human CD8 + T Cell Receptor Repertoire

Cited by 368 publications

References 15 publications

Determinants of public T cell responses

Determinants of public T cell responses

Half of the T‐cell repertoire combinatorial diversity is genetically determined in humans and humanized mice

Toll-Like Receptor 4 Agonist Injection With Concurrent Radiotherapy in Patients With Metastatic Soft Tissue Sarcoma

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Overlap and Effective Size of the Human CD8 ⁺ T Cell Receptor Repertoire