scholarly journals TCRβ Sequencing Reveals Spatial and Temporal Evolution of Clonal CD4 T Cell Responses in a Breach of Tolerance Model of Inflammatory Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Shaima Al Khabouri ◽  
Robert A. Benson ◽  
Catriona T. Prendergast ◽  
Joshua I. Gray ◽  
Thomas D. Otto ◽  
...  

Effective tolerogenic intervention in Rheumatoid Arthritis (RA) will rely upon understanding the evolution of articular antigen specific CD4 T cell responses. TCR clonality of endogenous CD4 T cell infiltrates in early inflammatory arthritis was assessed to monitor evolution of the TCR repertoire in the inflamed joint and associated lymph node (LN). Mouse models of antigen-induced breach of self-tolerance and chronic polyarthritis were used to recapitulate early and late phases of RA. The infiltrating endogenous, antigen experienced CD4 T cells in inflamed joints and LNs were analysed using flow cytometry and TCRβ sequencing. TCR repertoires from inflamed late phase LNs displayed increased clonality and diversity compared to early phase LNs, while inflamed joints remained similar with time. Repertoires from late phase LNs accumulated clones with a diverse range of TRBV genes, while inflamed joints at both phases contained clones expressing similar TRBV genes. Repertoires from LNs and joints at the late phase displayed reduced CDR3β sequence overlap compared to the early disease phase, however the most abundant clones in LNs accumulate in the joint at the later phase. The results indicate CD4 T cell repertoire clonality and diversity broadens with progression of inflammatory arthritis and is first reflected in LNs before mirroring in the joint. These observations imply that antigen specific tolerogenic therapies could be more effective if targeted at earlier phases of disease when CD4 T cell clonality is least diverse.

2020 ◽  
Author(s):  
Shaima Al-Khabouri ◽  
Robert A. Benson ◽  
Catriona T. Prendergast ◽  
Joshua I. Gray ◽  
Thomas D Otto ◽  
...  

ABSTRACTObjectivesDevelopment of effective tolerogenic therapies for Rheumatoid Arthritis (RA) relies on understanding the evolution of articular antigen specific CD4 T cell responses. TCR clonality of the endogenous CD4 T cell infiltrate in early inflammatory arthritis was assessed to monitor the evolution of the TCR repertoire in the inflamed joint and its associated popliteal lymph node (pLN).MethodsMouse models of antigen-induced breach of self-tolerance and chronic polyarthritis were used to recapitulate the early and late phases of RA reported in patients. The infiltrating endogenous, antigen experienced CD4 T cells in inflamed joints and pLNs were analysed using flow cytometry and TCRβ sequencing.ResultsTCR repertoires from pLNs displayed increased clonality and diversity with disease progression, while inflamed joints maintain similar TCR repertoire clonality and diversity with time. Repertoires from late phase pLNs accumulated clones with a diverse range TRBV genes, while inflamed joints at both phases contain clones expressing similar TRBV genes. Repertoires from pLNs and joints at the late phase displayed reduced CDR3β sequence overlap compared to the early disease phase, however correlation analysis revealed the most abundant clones in pLNs accumulate in the joint at the later phase.ConclusionsCD4 T cell clonality broadens and evolves with progression of inflammatory arthritis and is reflected in pLNs before potentially being mirrored in the joint. These observations imply that antigen specific tolerogenic therapies for RA will be more easily developed and more effective at earlier phases of the disease, when CD4 T cell clonality is least diverse.KEY MESSAGESSelective accumulation of CD4 T cell clones has been observed in arthritic joints of RA patients, indicating the presence of antigen driven accumulation of CD4 T cells in these patients.These antigen specific T cell clones are thought to be pathogenic and thus are targets for tolerogenic therapy.This study suggests that CD4 TCR clonality is restricted at the early phases of disease and broadens with disease progression. Moreover, changes in CD4 TCR clonality are first reflected in joint draining lymph nodes before being mirrored in the inflamed joint.Thus tolerogenic therapies will be more effective when CD4 TCR clonality is restricted i.e. at early disease stages.Changes in CD4 TCR clonality in the joint draining lymph node can also be a biomarker for disease state.


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