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Estimating T-cell repertoire diversity: limitations of classical estimators and a new approach.

Laydon DJ, Bangham CR, Asquith B - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2015)

Bottom Line: This is analogous to the 'unseen species problem' in ecology.We show that existing approaches have significant shortcomings, and frequently underestimate true TCR diversity.We highlight our recently developed estimator, DivE, which can accurately estimate diversity across a range of immunological and biological systems.

View Article: PubMed Central - PubMed

Affiliation: Section of Immunology, Wright-Fleming Institute, Imperial College School of Medicine, London W2 1PG, UK.

ABSTRACT
A highly diverse T-cell receptor (TCR) repertoire is a fundamental property of an effective immune system, and is associated with efficient control of viral infections and other pathogens. However, direct measurement of total TCR diversity is impossible. The diversity is high and the frequency distribution of individual TCRs is heavily skewed; the diversity therefore cannot be captured in a blood sample. Consequently, estimators of the total number of TCR clonotypes that are present in the individual, in addition to those observed, are essential. This is analogous to the 'unseen species problem' in ecology. We review the diversity (species richness) estimators that have been applied to T-cell repertoires and the methods used to validate these estimators. We show that existing approaches have significant shortcomings, and frequently underestimate true TCR diversity. We highlight our recently developed estimator, DivE, which can accurately estimate diversity across a range of immunological and biological systems.

No MeSH data available.


Related in: MedlinePlus

T-cell receptor gene rearrangement. (a) Variable (V), joining (J) and constant regions (C) constitute the TCR α-chain. (b) Variable (V), joining (J) and constant regions (C) constitute the TCR β-chain, with an additional diversity (D) region. Segments from each region are recombined, with additional nucleotide additions, to generate each rearranged TCR. These processes generate substantial T cell diversity. (c,d) Hypervariable complementarity-determining regions (CDR1-CDR3) of the α-chain (c) and β-chain (d). CDR1 and CDR2 regions are encoded on the V region, while the most variable CDR3 region straddles the V(D)J junction.
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RSTB20140291F1: T-cell receptor gene rearrangement. (a) Variable (V), joining (J) and constant regions (C) constitute the TCR α-chain. (b) Variable (V), joining (J) and constant regions (C) constitute the TCR β-chain, with an additional diversity (D) region. Segments from each region are recombined, with additional nucleotide additions, to generate each rearranged TCR. These processes generate substantial T cell diversity. (c,d) Hypervariable complementarity-determining regions (CDR1-CDR3) of the α-chain (c) and β-chain (d). CDR1 and CDR2 regions are encoded on the V region, while the most variable CDR3 region straddles the V(D)J junction.

Mentions: TCRs are heterodimers and fall into two classes: TCR-αβ and TCR-γδ; γδ T cells constitute 1–10% of the T-cell repertoire [4]. A variable (V), joining (J) and constant region (C) constitute the TCR α- and γ-chains. The TCR β- and δ-chains are also made up of a V, J and C region, with an additional diversity (D) region [5]. One segment from each region is recombined, with additional nucleotide additions and/or deletions, to generate each rearranged TCR (figure 1). This recombination generates high T-cell diversity [1] and enables the recognition of millions of antigens [6]. While V(D)J gene rearrangement is believed to be random [7], some clonotypes are produced more commonly than others [2,8], leading to unequal frequencies of naive T-cell clonotypes and to ‘public’ clonotypes, i.e. clonotypes shared between people. This unequal frequency distribution is believed to be due to a process known as convergent recombination, whereby certain nucleotide sequences can be produced using a greater variety of recombination events; certain amino acid sequences can be made by a greater number of nucleotide triplets; and certain TCRs require fewer nucleotide insertions, deletions or substitutions [9].Figure 1.


Estimating T-cell repertoire diversity: limitations of classical estimators and a new approach.

Laydon DJ, Bangham CR, Asquith B - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2015)

T-cell receptor gene rearrangement. (a) Variable (V), joining (J) and constant regions (C) constitute the TCR α-chain. (b) Variable (V), joining (J) and constant regions (C) constitute the TCR β-chain, with an additional diversity (D) region. Segments from each region are recombined, with additional nucleotide additions, to generate each rearranged TCR. These processes generate substantial T cell diversity. (c,d) Hypervariable complementarity-determining regions (CDR1-CDR3) of the α-chain (c) and β-chain (d). CDR1 and CDR2 regions are encoded on the V region, while the most variable CDR3 region straddles the V(D)J junction.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4528489&req=5

RSTB20140291F1: T-cell receptor gene rearrangement. (a) Variable (V), joining (J) and constant regions (C) constitute the TCR α-chain. (b) Variable (V), joining (J) and constant regions (C) constitute the TCR β-chain, with an additional diversity (D) region. Segments from each region are recombined, with additional nucleotide additions, to generate each rearranged TCR. These processes generate substantial T cell diversity. (c,d) Hypervariable complementarity-determining regions (CDR1-CDR3) of the α-chain (c) and β-chain (d). CDR1 and CDR2 regions are encoded on the V region, while the most variable CDR3 region straddles the V(D)J junction.
Mentions: TCRs are heterodimers and fall into two classes: TCR-αβ and TCR-γδ; γδ T cells constitute 1–10% of the T-cell repertoire [4]. A variable (V), joining (J) and constant region (C) constitute the TCR α- and γ-chains. The TCR β- and δ-chains are also made up of a V, J and C region, with an additional diversity (D) region [5]. One segment from each region is recombined, with additional nucleotide additions and/or deletions, to generate each rearranged TCR (figure 1). This recombination generates high T-cell diversity [1] and enables the recognition of millions of antigens [6]. While V(D)J gene rearrangement is believed to be random [7], some clonotypes are produced more commonly than others [2,8], leading to unequal frequencies of naive T-cell clonotypes and to ‘public’ clonotypes, i.e. clonotypes shared between people. This unequal frequency distribution is believed to be due to a process known as convergent recombination, whereby certain nucleotide sequences can be produced using a greater variety of recombination events; certain amino acid sequences can be made by a greater number of nucleotide triplets; and certain TCRs require fewer nucleotide insertions, deletions or substitutions [9].Figure 1.

Bottom Line: This is analogous to the 'unseen species problem' in ecology.We show that existing approaches have significant shortcomings, and frequently underestimate true TCR diversity.We highlight our recently developed estimator, DivE, which can accurately estimate diversity across a range of immunological and biological systems.

View Article: PubMed Central - PubMed

Affiliation: Section of Immunology, Wright-Fleming Institute, Imperial College School of Medicine, London W2 1PG, UK.

ABSTRACT
A highly diverse T-cell receptor (TCR) repertoire is a fundamental property of an effective immune system, and is associated with efficient control of viral infections and other pathogens. However, direct measurement of total TCR diversity is impossible. The diversity is high and the frequency distribution of individual TCRs is heavily skewed; the diversity therefore cannot be captured in a blood sample. Consequently, estimators of the total number of TCR clonotypes that are present in the individual, in addition to those observed, are essential. This is analogous to the 'unseen species problem' in ecology. We review the diversity (species richness) estimators that have been applied to T-cell repertoires and the methods used to validate these estimators. We show that existing approaches have significant shortcomings, and frequently underestimate true TCR diversity. We highlight our recently developed estimator, DivE, which can accurately estimate diversity across a range of immunological and biological systems.

No MeSH data available.


Related in: MedlinePlus