A Mechanism for TCR Sharing between T Cell Subsets and Individuals Revealed by Pyrosequencing

Venturi, Vanessa; Quigley, Máire F.; Greenaway, Hui Yee; Ng, Pauline C.; Ende, Zachary; McIntosh, Tina C; Asher, Tedi E.; Almeida, Jorge Reis; Lévy, Samuel; Price, David A.; Davenport, Miles P.; Douek, Daniel C.

doi:10.4049/jimmunol.1003898

Cited by 178 publications

(221 citation statements)

References 46 publications

Supporting

Mentioning

203

Contrasting

Order By: Relevance

“…The results are consistent with experimental data (9) showing that naive CD4 T cell proliferation rate doubles after the age of 70 y coincident with a sharp decline of T cell diversity. These results, which were obtained by assuming that there is a strong bias in the production frequencies of different T cell clones (i.e., w = 0.01) consistent with empirical data (46,47,60), are similar to results obtained without such bias (Supplemental Fig. 1).…”

Section: Effective Clonal Diversity Declines Sharply In Old Agesupporting

confidence: 84%

“…We sample individual clones from the distribution G(i), where i, i = 1,..., S, is a clonal index, and G(i) is the expected frequency of clone i. Empirical data indicate that different clones have very different a priori production frequencies (60), with the fold difference between the highest and lowest frequencies being on the order of 10 4 (46,47). This implies that G(i) must be highly biased.…”

Section: Effective Clonal Diversity Declines Sharply In Old Agementioning

confidence: 99%

See 1 more Smart Citation

The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells

Ndifon

Dushoff

2016

The Journal of Immunology

View full text Add to dashboard Cite

Having a large number of sufficiently abundant T cell clones is important for adequate protection against diseases. However, as shown in this paper and elsewhere, between young adulthood and >70 y of age the effective clonal diversity of naive CD4/CD8 T cells found in human blood declines by a factor of >10. (Effective clonal diversity accounts for both the number and the abundance of T cell clones.) The causes of this observation are incompletely understood. A previous study proposed that it might result from the emergence of certain rare, replication-enhancing mutations in T cells. In this paper, we propose an even simpler explanation: that it results from the loss of T cells that have attained replicative senescence (i.e., the Hayflick limit). Stochastic numerical simulations of naive T cell population dynamics, based on experimental parameters, show that the rate of homeostatic T cell proliferation increases after the age of ∼60 y because naive T cells collectively approach replicative senescence. This leads to a sharp decline of effective clonal diversity after ∼70 y, in agreement with empirical data. A mathematical analysis predicts that, without an increase in the naive T cell proliferation rate, this decline will occur >50 yr later than empirically observed. These results are consistent with a model in which exhaustion of the proliferative capacity of naive T cells causes a sharp decline of their effective clonal diversity and imply that therapeutic potentiation of thymopoiesis might either prevent or reverse this outcome.

show abstract

Section: Effective Clonal Diversity Declines Sharply In Old Agesupporting

confidence: 84%

Section: Effective Clonal Diversity Declines Sharply In Old Agementioning

confidence: 99%

The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells

Ndifon

Dushoff

2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…However, when converted into amino acid sequences, the conservation appeared much higher with up to 14.2% homology between two unrelated donors [8]. Furthermore, a recent study argue that 424.5% of the naïve TCRb amino acid repertoire was shared with at least another donor of the study [9]. These results are in line with our observation that a significant portion of the repertoire is shared among different human donors and humanized mice.…”

Section: Discussionsupporting

confidence: 90%

“…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

View full text Add to dashboard Cite

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...

show abstract

“…In this hypothesis, shared TCRs are simply those that have a higher‐than‐average generation probability and are thus more abundant in the unselected repertoire 13. The advent of high‐throughput sequencing of TCR repertoires14, 15, 16, 17 has largely confirmed this view through the analysis of shared TCR sequences between unrelated humans,18, 19, 20 monozygous human twins,21, 22 and mice 23. However, despite recent efforts to characterize the landscape of public TCRs,24 the contributions of V(D)J generation biases and convergent recombination relative to convergent selection remain to be elucidated and quantified.…”

Section: Introductionmentioning

confidence: 99%

Predicting the spectrum of TCR repertoire sharing with a data‐driven model of recombination

Elhanati

Sethna

Callan

et al. 2018

Immunological Reviews

128

159

View full text Add to dashboard Cite

SummaryDespite the extreme diversity of T‐cell repertoires, many identical T‐cell receptor (TCR) sequences are found in a large number of individual mice and humans. These widely shared sequences, often referred to as “public,” have been suggested to be over‐represented due to their potential immune functionality or their ease of generation by V(D)J recombination. Here, we show that even for large cohorts, the observed degree of sharing of TCR sequences between individuals is well predicted by a model accounting for the known quantitative statistical biases in the generation process, together with a simple model of thymic selection. Whether a sequence is shared by many individuals is predicted to depend on the number of queried individuals and the sampling depth, as well as on the sequence itself, in agreement with the data. We introduce the degree of publicness conditional on the queried cohort size and the size of the sampled repertoires. Based on these observations, we propose a public/private sequence classifier, “PUBLIC” (Public Universal Binary Likelihood Inference Classifier), based on the generation probability, which performs very well even for small cohort sizes.

show abstract

A Mechanism for TCR Sharing between T Cell Subsets and Individuals Revealed by Pyrosequencing

Cited by 178 publications

References 46 publications

The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells

The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells

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

Predicting the spectrum of TCR repertoire sharing with a data‐driven model of recombination

Contact Info

Product

Resources

About