The T Cell Receptor Repertoire in Neuropsychiatric Systemic Lupus Erythematosus.

Erica Moore,Samantha A Chalmers,Michelle W Huang,Shweta Jain,Fernando Macian,Chaim Putterman

doi:10.3389/fimmu.2020.01476

Erica Moore, Samantha A Chalmers + Show 4 more

Open Access

https://doi.org/10.3389/fimmu.2020.01476

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Abstract

Objective: In systemic lupus erythematosus (SLE), widespread T cell infiltration into target organs contributes to inflammation and organ damage. Autoreactive T cells become aberrantly activated in this disease due to dysfunctional T cell receptor signaling that lowers the activation threshold. Characterizing the T cell repertoire can provide further insight into the specific homing and proliferation of these T cells into lupus target organs. In the spontaneous lupus model, MRL/lpr, the TCR repertoire has not been fully elucidated, especially for T cells infiltrating the brain. Our aim was to investigate and compare the TCR repertoire between MRL/lpr mice and its congenic controls, MRL/MpJ, and within MRL/lpr tissues.Methods: Spleen, salivary gland, and brain choroid plexus were isolated from female MRL/lpr mice and MRL/MpJ mice. The TCRβ CDR3 region was analyzed by multiplex PCRs and sequencing.Results: Significant differences were seen not only between the MRL/lpr and MRL/MpJ spleens, but also between MRL/lpr tissues. The TCR repertoire in MRL/lpr choroid plexus tissues had significantly increased clonality and sequence homology compared to MRL/lpr spleen and salivary gland. The consensus sequence, CASSQDWGGYEQYFF, was identified in the MRL/lpr choroid plexus repertoire.Conclusions: The TCR repertoire in lupus prone mice is not uniform between target organs, and suggests that T cells are specifically recruited into the choroid plexus of MRL/lpr mice. Further studies are needed to determine the antigen specificities for these infiltrating T cells in target organs of lupus mice, and their possible contribution to the pathogenesis of neuropsychiatric disease and other lupus manifestations.

Highlights

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the formation of autoantibodies and immune complexes, and the presence of autoreactive T cells
T cells recognize a complex of human leukocyte antigen (HLA) molecules and antigenic peptides, which mediates the interaction between T cells and antigen-presenting cells
Alterations in the T cell receptor (TCR) repertoire have been found in multiple autoimmune diseases, including SLE, rheumatoid arthritis, and Type 1 diabetes mellitus, and are implicated in the breakdown of peripheral immune tolerance [8,9,10,11,12,13,14]

Summary

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the formation of autoantibodies and immune complexes, and the presence of autoreactive T cells. In SLE, these autoreactive T cells are integral in disease pathogenesis by propagating inflammatory cytokine secretion, facilitating autoantibody formation via B cell help, and differentiating into autoreactive memory T cells [1,2,3,4,5]. These inflammatory effects are further exaggerated by the aberrant infiltration of these T cells into organs, causing subsequent damage and injury. The complementarity-determining region 3 (CDR3) loops are positioned to interact with the presented antigenic peptide and is considered to be the most diverse segment This recognition leads to the activation and proliferation of antigen-specific T cells [7]. Analyzing the repertoire of clonally expanded T cells can potentially reveal specific homing of these T cells based on local antigen-driven activation

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