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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

Skewing of the TCR repertoire in human disease. The peripheral TCR repertoire is shaped by antigen encounter and altered in the context of disease. Classical pMHC recognition leads to clonal expansion of antigen-specific T cells, which in some human pathologies can lead to extreme oligoclonality and skewing (top). In this setting, the expansion of public clonotypes can be beneficial as seen in HIV-1 infection, but in other cases, certain clonotypes are involved in disease pathogenesis as described for MS. Other semi-invariant clonotypes such as iNKT (also called NKT type I), MAIT and GEM TCRs expand in response to some microbial infections in an HLA-independent manner (centre). Some malignancies such as ALL, or other disorders associated with chromosomal instability, provoke the expansion of aberrant clonotypes (Ig/TCR hybrids or TCR-γ/TCR-β hybrids; bottom) that are largely absent from the healthy. ALL, acute lymphoid leukaemia; GEM, germline-encoded, mycoyl-reactive; iNKT, invariant natural killer T; MAIT, mucosa-associated invariant T; MS, multiple sclerosis; pMHC, peptide-major histocompatibility complex; TCR, T cell receptor.
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fig4: Skewing of the TCR repertoire in human disease. The peripheral TCR repertoire is shaped by antigen encounter and altered in the context of disease. Classical pMHC recognition leads to clonal expansion of antigen-specific T cells, which in some human pathologies can lead to extreme oligoclonality and skewing (top). In this setting, the expansion of public clonotypes can be beneficial as seen in HIV-1 infection, but in other cases, certain clonotypes are involved in disease pathogenesis as described for MS. Other semi-invariant clonotypes such as iNKT (also called NKT type I), MAIT and GEM TCRs expand in response to some microbial infections in an HLA-independent manner (centre). Some malignancies such as ALL, or other disorders associated with chromosomal instability, provoke the expansion of aberrant clonotypes (Ig/TCR hybrids or TCR-γ/TCR-β hybrids; bottom) that are largely absent from the healthy. ALL, acute lymphoid leukaemia; GEM, germline-encoded, mycoyl-reactive; iNKT, invariant natural killer T; MAIT, mucosa-associated invariant T; MS, multiple sclerosis; pMHC, peptide-major histocompatibility complex; TCR, T cell receptor.

Mentions: Using ‘next-generation' sequencing, a more recent study in three pairs of healthy, monozygotic twins suggested that the composition of the TCR repertoire at the CDR3 level was also largely determined by genetic factors.57 V segment usage in out-of-frame sequences was found to be more similar in twins than in non-twins, indicating a genetically determined bias prior to selection, in line with had been previously reported by Genolet et al.20 Remarkably, monozygotic twins did not share more in-frame sequences with their twin than with an unrelated individual, indicating that certain TCR clonotypes can be enriched and shared across a wide population irrespective of HLA type, as previously suggested by Robins et al.38 This is in accordance with previous studies highlighting convergent recombination as a major route for the generation of public TCRs. Some of the sequences shared by multiple, unrelated individuals may be enriched with clonotypes derived from invariant populations such as invariant natural killer T cells, mucosa-associated invariant T cells and germline-encoded, mycoyl-reactive T cells.58 Such semi-invariant TCRs are likely raised against common antigens and shared across the population. Thus, if linked to certain infections, such TCRs could become invaluable tools for the diagnosis of human disease (Figure 4).


αβ T cell receptors as predictors of health and disease.

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

Skewing of the TCR repertoire in human disease. The peripheral TCR repertoire is shaped by antigen encounter and altered in the context of disease. Classical pMHC recognition leads to clonal expansion of antigen-specific T cells, which in some human pathologies can lead to extreme oligoclonality and skewing (top). In this setting, the expansion of public clonotypes can be beneficial as seen in HIV-1 infection, but in other cases, certain clonotypes are involved in disease pathogenesis as described for MS. Other semi-invariant clonotypes such as iNKT (also called NKT type I), MAIT and GEM TCRs expand in response to some microbial infections in an HLA-independent manner (centre). Some malignancies such as ALL, or other disorders associated with chromosomal instability, provoke the expansion of aberrant clonotypes (Ig/TCR hybrids or TCR-γ/TCR-β hybrids; bottom) that are largely absent from the healthy. ALL, acute lymphoid leukaemia; GEM, germline-encoded, mycoyl-reactive; iNKT, invariant natural killer T; MAIT, mucosa-associated invariant T; MS, multiple sclerosis; pMHC, peptide-major histocompatibility complex; TCR, T cell receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Skewing of the TCR repertoire in human disease. The peripheral TCR repertoire is shaped by antigen encounter and altered in the context of disease. Classical pMHC recognition leads to clonal expansion of antigen-specific T cells, which in some human pathologies can lead to extreme oligoclonality and skewing (top). In this setting, the expansion of public clonotypes can be beneficial as seen in HIV-1 infection, but in other cases, certain clonotypes are involved in disease pathogenesis as described for MS. Other semi-invariant clonotypes such as iNKT (also called NKT type I), MAIT and GEM TCRs expand in response to some microbial infections in an HLA-independent manner (centre). Some malignancies such as ALL, or other disorders associated with chromosomal instability, provoke the expansion of aberrant clonotypes (Ig/TCR hybrids or TCR-γ/TCR-β hybrids; bottom) that are largely absent from the healthy. ALL, acute lymphoid leukaemia; GEM, germline-encoded, mycoyl-reactive; iNKT, invariant natural killer T; MAIT, mucosa-associated invariant T; MS, multiple sclerosis; pMHC, peptide-major histocompatibility complex; TCR, T cell receptor.
Mentions: Using ‘next-generation' sequencing, a more recent study in three pairs of healthy, monozygotic twins suggested that the composition of the TCR repertoire at the CDR3 level was also largely determined by genetic factors.57 V segment usage in out-of-frame sequences was found to be more similar in twins than in non-twins, indicating a genetically determined bias prior to selection, in line with had been previously reported by Genolet et al.20 Remarkably, monozygotic twins did not share more in-frame sequences with their twin than with an unrelated individual, indicating that certain TCR clonotypes can be enriched and shared across a wide population irrespective of HLA type, as previously suggested by Robins et al.38 This is in accordance with previous studies highlighting convergent recombination as a major route for the generation of public TCRs. Some of the sequences shared by multiple, unrelated individuals may be enriched with clonotypes derived from invariant populations such as invariant natural killer T cells, mucosa-associated invariant T cells and germline-encoded, mycoyl-reactive T cells.58 Such semi-invariant TCRs are likely raised against common antigens and shared across the population. Thus, if linked to certain infections, such TCRs could become invaluable tools for the diagnosis of human disease (Figure 4).

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