Limits...
αβ T cell receptors as predictors of health and disease.

Attaf M, Huseby E, Sewell AK - Cell. Mol. Immunol. (2015)

Bottom Line: However, a number of immune responses are associated with the selection of predictable, narrow, or skewed repertoires and public TCR chains.Here, we summarize the current knowledge on the formation of the TCR repertoire and its maintenance in health and disease.We also outline the various molecular mechanisms that govern the composition of the pre-selection, naive and antigen-specific TCR repertoires.

View Article: PubMed Central - PubMed

Affiliation: Cardiff University School of Medicine, Cardiff, UK.

ABSTRACT
The diversity of antigen receptors and the specificity it underlies are the hallmarks of the cellular arm of the adaptive immune system. T and B lymphocytes are indeed truly unique in their ability to generate receptors capable of recognizing virtually any pathogen. It has been known for several decades that T lymphocytes recognize short peptides derived from degraded proteins presented by major histocompatibility complex (MHC) molecules at the cell surface. Interaction between peptide-MHC (pMHC) and the T cell receptor (TCR) is central to both thymic selection and peripheral antigen recognition. It is widely assumed that TCR diversity is required, or at least highly desirable, to provide sufficient immune coverage. However, a number of immune responses are associated with the selection of predictable, narrow, or skewed repertoires and public TCR chains. Here, we summarize the current knowledge on the formation of the TCR repertoire and its maintenance in health and disease. We also outline the various molecular mechanisms that govern the composition of the pre-selection, naive and antigen-specific TCR repertoires. Finally, we suggest that with the development of high-throughput sequencing, common TCR 'signatures' raised against specific antigens could provide important diagnostic biomarkers and surrogate predictors of disease onset, progression and outcome.

No MeSH data available.


Related in: MedlinePlus

Gene rearrangement at the tr loci. (a) VJ recombination at the tra locus. The tra locus (in which the TCR-δ, or trd locus is also embedded) comprises a 5′ V gene segment cluster (46 TRAV segments) followed by a central J cluster (51 TRAJ segments) and a single C gene segment (TRAC). TCR-δ D and J segments (TRDD and TRDJ, respectively) are also present in the locus. V to J recombination brings together one of many TRAV segments to one of many TRAJ segments. The intervening sequences are spliced out, producing a TCR-α transcript in which V, J and C segments are directly adjacent. (b) VDJ recombination at the trb locus. The trb locus is composed of a 5′ V cluster (48 TRBV gene segments) followed by two 3′ TRBD–TRBJ–TRBC clusters. VDJ recombination is a two-step, ordered process. D to J recombination occurs first, juxtaposing TRBD1 to one of the six TRBJ1 segments or TRBD2 to one the seven TRBJ2 segments. V to DJ recombination subsequently brings the rearranged DJ join to one of many TRBV segments. The intervening sequences are then spliced out, generating a TCR-β transcript in which, V, D, J and C segments are directly adjacent. TCR, T cell receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4496535&req=5

fig2: Gene rearrangement at the tr loci. (a) VJ recombination at the tra locus. The tra locus (in which the TCR-δ, or trd locus is also embedded) comprises a 5′ V gene segment cluster (46 TRAV segments) followed by a central J cluster (51 TRAJ segments) and a single C gene segment (TRAC). TCR-δ D and J segments (TRDD and TRDJ, respectively) are also present in the locus. V to J recombination brings together one of many TRAV segments to one of many TRAJ segments. The intervening sequences are spliced out, producing a TCR-α transcript in which V, J and C segments are directly adjacent. (b) VDJ recombination at the trb locus. The trb locus is composed of a 5′ V cluster (48 TRBV gene segments) followed by two 3′ TRBD–TRBJ–TRBC clusters. VDJ recombination is a two-step, ordered process. D to J recombination occurs first, juxtaposing TRBD1 to one of the six TRBJ1 segments or TRBD2 to one the seven TRBJ2 segments. V to DJ recombination subsequently brings the rearranged DJ join to one of many TRBV segments. The intervening sequences are then spliced out, generating a TCR-β transcript in which, V, D, J and C segments are directly adjacent. TCR, T cell receptor.

Mentions: The TCR is a heterodimer of one α and one β chain, or one γ and one δ chain, which are disulphide-linked.3,4 Each TCR chain is composed of a constant and a variable domain, followed by a membrane-spanning region and a short cytosolic tail. Diversity in the TCR is predominantly confined to six hypervariable hairpin loops in the variable domains, called complementarity-determining regions5 (CDR) (Figure 1a). TCR chains are assembled somatically during T cell development by the joining of discrete V, (D) and J gene segments by recombination activating gene (RAG)1 and RAG2 (Figures 1b and 2). The process of V (D) J recombination is such that CDR1α, CDR1β, CDR2α and CDR2β are entirely encoded in germline DNA segments. In contrast, the CDR3 loops are the product of junctional diversity and are consequently hypervariable (Figure 1b).


αβ T cell receptors as predictors of health and disease.

Attaf M, Huseby E, Sewell AK - Cell. Mol. Immunol. (2015)

Gene rearrangement at the tr loci. (a) VJ recombination at the tra locus. The tra locus (in which the TCR-δ, or trd locus is also embedded) comprises a 5′ V gene segment cluster (46 TRAV segments) followed by a central J cluster (51 TRAJ segments) and a single C gene segment (TRAC). TCR-δ D and J segments (TRDD and TRDJ, respectively) are also present in the locus. V to J recombination brings together one of many TRAV segments to one of many TRAJ segments. The intervening sequences are spliced out, producing a TCR-α transcript in which V, J and C segments are directly adjacent. (b) VDJ recombination at the trb locus. The trb locus is composed of a 5′ V cluster (48 TRBV gene segments) followed by two 3′ TRBD–TRBJ–TRBC clusters. VDJ recombination is a two-step, ordered process. D to J recombination occurs first, juxtaposing TRBD1 to one of the six TRBJ1 segments or TRBD2 to one the seven TRBJ2 segments. V to DJ recombination subsequently brings the rearranged DJ join to one of many TRBV segments. The intervening sequences are then spliced out, generating a TCR-β transcript in which, V, D, J and C segments are directly adjacent. TCR, T cell receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496535&req=5

fig2: Gene rearrangement at the tr loci. (a) VJ recombination at the tra locus. The tra locus (in which the TCR-δ, or trd locus is also embedded) comprises a 5′ V gene segment cluster (46 TRAV segments) followed by a central J cluster (51 TRAJ segments) and a single C gene segment (TRAC). TCR-δ D and J segments (TRDD and TRDJ, respectively) are also present in the locus. V to J recombination brings together one of many TRAV segments to one of many TRAJ segments. The intervening sequences are spliced out, producing a TCR-α transcript in which V, J and C segments are directly adjacent. (b) VDJ recombination at the trb locus. The trb locus is composed of a 5′ V cluster (48 TRBV gene segments) followed by two 3′ TRBD–TRBJ–TRBC clusters. VDJ recombination is a two-step, ordered process. D to J recombination occurs first, juxtaposing TRBD1 to one of the six TRBJ1 segments or TRBD2 to one the seven TRBJ2 segments. V to DJ recombination subsequently brings the rearranged DJ join to one of many TRBV segments. The intervening sequences are then spliced out, generating a TCR-β transcript in which, V, D, J and C segments are directly adjacent. TCR, T cell receptor.
Mentions: The TCR is a heterodimer of one α and one β chain, or one γ and one δ chain, which are disulphide-linked.3,4 Each TCR chain is composed of a constant and a variable domain, followed by a membrane-spanning region and a short cytosolic tail. Diversity in the TCR is predominantly confined to six hypervariable hairpin loops in the variable domains, called complementarity-determining regions5 (CDR) (Figure 1a). TCR chains are assembled somatically during T cell development by the joining of discrete V, (D) and J gene segments by recombination activating gene (RAG)1 and RAG2 (Figures 1b and 2). The process of V (D) J recombination is such that CDR1α, CDR1β, CDR2α and CDR2β are entirely encoded in germline DNA segments. In contrast, the CDR3 loops are the product of junctional diversity and are consequently hypervariable (Figure 1b).

Bottom Line: However, a number of immune responses are associated with the selection of predictable, narrow, or skewed repertoires and public TCR chains.Here, we summarize the current knowledge on the formation of the TCR repertoire and its maintenance in health and disease.We also outline the various molecular mechanisms that govern the composition of the pre-selection, naive and antigen-specific TCR repertoires.

View Article: PubMed Central - PubMed

Affiliation: Cardiff University School of Medicine, Cardiff, UK.

ABSTRACT
The diversity of antigen receptors and the specificity it underlies are the hallmarks of the cellular arm of the adaptive immune system. T and B lymphocytes are indeed truly unique in their ability to generate receptors capable of recognizing virtually any pathogen. It has been known for several decades that T lymphocytes recognize short peptides derived from degraded proteins presented by major histocompatibility complex (MHC) molecules at the cell surface. Interaction between peptide-MHC (pMHC) and the T cell receptor (TCR) is central to both thymic selection and peripheral antigen recognition. It is widely assumed that TCR diversity is required, or at least highly desirable, to provide sufficient immune coverage. However, a number of immune responses are associated with the selection of predictable, narrow, or skewed repertoires and public TCR chains. Here, we summarize the current knowledge on the formation of the TCR repertoire and its maintenance in health and disease. We also outline the various molecular mechanisms that govern the composition of the pre-selection, naive and antigen-specific TCR repertoires. Finally, we suggest that with the development of high-throughput sequencing, common TCR 'signatures' raised against specific antigens could provide important diagnostic biomarkers and surrogate predictors of disease onset, progression and outcome.

No MeSH data available.


Related in: MedlinePlus