High Throughput Human T Cell Receptor Sequencing: A New Window Into Repertoire Establishment and Alloreactivity

Fu, Jianing; Khosravi‐Maharlooei, Mohsen; Sykes, Megan

doi:10.3389/fimmu.2021.777756

Cited by 10 publications

(7 citation statements)

References 117 publications

(159 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Antigen targets of the sequenced TCRs were determined using online databases on known TCR–antigen pairs 26–28 . RNA‐level sequencing of TCRs was implemented due to the accessibility, reliability, and previously shown efficacy of RNA TCR repertoire analysis 29–32 …”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Similarity Network Analysis of the Adaptive Immune Response in the Proximal Airway

Clark,

Talatala,

et al. 2024

The Laryngoscope

View full text Add to dashboard Cite

ObjectivesRecent immunologic study of the adaptive immune repertoire in the subglottic airway demonstrated high‐frequency T cell clones that do not overlap between individuals. However, the anatomic distribution and antigenic target of the T cell repertoire in the proximal airway mucosa remain unresolved.MethodsSingle‐cell RNA sequencing of matched scar and unaffected mucosa from idiopathic subglottic stenosis patients (iSGS, n = 32) was performed and compared with airway mucosa from healthy controls (n = 10). T cell receptor (TCR) sequences were interrogated via similarity network analysis to explore antigenic targets using the published algorithm: Grouping of Lymphocyte Interactions by Paratope Hotspots (GLIPH2).ResultsThe mucosal T cell repertoire in healthy control airways consisted of highly expressed T cell clones conserved across anatomic subsites (trachea, bronchi, bronchioles, and lung). In iSGS, high‐frequency clones were equally represented in both scar and adjacent non‐scar tissue. Significant differences in repertoire structure between iSGS scar and unaffected mucosa was observed, driven by unique low‐frequency clones. GLIPH2 results suggest low‐frequency clones share targets between multiple iSGS patients.ConclusionHealthy airway mucosa has a highly conserved T cell repertoire across multiple anatomic subsites. Similarly, iSGS patients have highly expressed T cell clones present in both scar and unaffected mucosa. iSGS airway scar possesses an abundance of less highly expanded clones with predicted antigen targets shared between patients. Interrogation of these shared motifs suggests abundant adaptive immunity to viral targets in iSGS airway scar. These results provide insight into disease pathogenesis and illuminate new treatment strategies in iSGS.Level of EvidenceLevel NA Laryngoscope, 2024

show abstract

Section: Methodsmentioning

confidence: 99%

“…[26][27][28] RNA-level sequencing of TCRs was implemented due to the accessibility, reliability, and previously shown efficacy of RNA TCR repertoire analysis. [29][30][31][32] Computational Analysis Tools-GLIPH2…”

Section: Tcr Sequencingmentioning

confidence: 99%

Similarity Network Analysis of the Adaptive Immune Response in the Proximal Airway

Clark,

Talatala,

et al. 2024

The Laryngoscope

View full text Add to dashboard Cite

show abstract

“…3,6 The purpose of the present paper, as with its predecessors, 4,7,8 has been to document the growing recognition of positive repertoire selection and its role in alloresponsiveness, and to suggest its mechanistic basis. 2 Results with mice 17 are being increasing confirmed for humans 9,18 and emphasize the role in generating the diversity of T cell subsets of the 'variable signal strengths' obtained during 'early encounters with subthreshold ligands in the thymus'. 19 An absence of T cell receptor cross-linking at low thymic ligand concentrations may be necessary for positive selection, 20 in keeping with a second inhibitory signal at higher concentrations, as discussed elsewhere.…”

Section: Why the Delay?mentioning

confidence: 96%

Positive selection of immune repertoires: A short further history

Forsdyke

2022

Scand J Immunol

View full text Add to dashboard Cite

The importance of the negative selection of self‐reacting cells from immune repertoires was easily recognized since it would militate against autoimmune disease. However, while the existence of positive selection in the auditioning of newly formed immune cells is now recognized, it is taking longer to understand its role. With the removal or suppression by negative selection of a subset of immune cells that self‐react, would the specificities of remaining immune cells range widely to confront the universe of ‘non‐self’ antigens, including some borne by potential microbial pathogens? Alternatively, from among those remaining immune cells, could some be picked out (positively selected) based on ‘advanced knowledge’ of some character likely to be common to those pathogens? To exploit ‘holes’ created by negative selection, it was predicted that pathogens would attempt to mimic their hosts by progressive stepwise mutation towards host ‘self’—a process entailing passage through a host anti‐‘near‐self‐reactivity’ arena. Anticipating this, those hosts that over evolutionary time ‘learned’ to positively select from developing immune repertoires, cells with reactivities against ‘near‐self’, would be advantaged by natural selection. The benefits of this narrowing of the range of host immune reactivities are now clearer and may solve Burnet's paradox, which concerns the ability of an organism's immune cells to attack its own cancer cells. However, while supporting this in the context of T cell immunity, Manczinger and his colleagues now suggest that some wily pathogens may be exploiting their hosts' narrow defence foci by ‘seeking’, through mutation, dissimilarity from host ‘self’.

show abstract

“…Indeed, the study of TCR repertoires using high-throughput sequencing (HTS) in solid organ and bone marrow stem cell transplantation proved to be a powerful tool capable of revealing many aspects of allorecognition and rejection [8,9]. The main achievement of this method is the possibility of assessing the severity of rejection and predicting the outcome of transplantation by tracking the alloreactive clonotypes identified in advance in mixed lymphocyte culture (MLC) with donor and recipient cells [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

TCR Sequencing in Mouse Models of Allorecognition Unveils the Features of Directly and Indirectly Activated Clonotypes

Tereshchenko

Shevyrev

Fisher

et al. 2023

IJMS

View full text Add to dashboard Cite

Allorecognition is known to involve a large number of lymphocytes carrying diverse T-cell receptor repertoire. Thus, one way to understand allorecognition and rejection mechanisms is via high-throughput sequencing of T-cell receptors. In this study, in order to explore and systematize the properties of the alloreactive T-cell receptor repertoire, we modeled direct and indirect allorecognition pathways using material from inbred mice in vitro and in vivo. Decoding of the obtained T-cell receptor genes using high-throughput sequencing revealed some features of the alloreactive repertoires. Thus, alloreactive T-cell receptor repertoires were characterized by specific V-gene usage patterns, changes in CDR3 loop length, and some amino acid occurrence probabilities in the CDR3 loop. Particularly pronounced changes were observed for directly alloreactive clonotypes. We also revealed a clustering of directly and indirectly alloreactive clonotypes by their ability to bind a single antigen; amino acid patterns of the CDR3 loop of alloreactive clonotypes; and the presence in alloreactive repertoires of clonotypes also associated with infectious, autoimmune, and tumor diseases. The obtained results were determined by the modeling of the simplified allorecognition reaction in inbred mice in which stimulation was performed with a single MHCII molecule. We suppose that the decomposition of the diverse alloreactive TCR repertoire observed in humans with transplants into such simple reactions will help to find alloreactive repertoire features; e.g., a dominant clonotype or V-gene usage pattern, which may be targeted to correct the entire rejection reaction in patients. In this work, we propose several technical ways for such decomposition analysis, including separate modeling of the indirect alloreaction pathway and clustering of alloreactive clonotypes according to their ability to bind a single antigen, among others.

show abstract

High Throughput Human T Cell Receptor Sequencing: A New Window Into Repertoire Establishment and Alloreactivity

Cited by 10 publications

References 117 publications

Similarity Network Analysis of the Adaptive Immune Response in the Proximal Airway

Similarity Network Analysis of the Adaptive Immune Response in the Proximal Airway

Positive selection of immune repertoires: A short further history

TCR Sequencing in Mouse Models of Allorecognition Unveils the Features of Directly and Indirectly Activated Clonotypes

Contact Info

Product

Resources

About