The evolution of CD4+ T cell clonality in a murine model of inflammatory arthritis

Al Khabouri, Shaima Mazin Jawad (2020) The evolution of CD4+ T cell clonality in a murine model of inflammatory arthritis. PhD thesis, University of Glasgow.

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Abstract

Immunological tolerance is an important aspect of immunity preventing responses being mounted against self-peptides and other innocuous foreign antigens. A breach in self-tolerance can lead to the development of autoimmune diseases such as Rheumatoid arthritis (RA). RA is a chronic inflammatory autoimmune disease that is characterised by synovial inflammation and joint erosion. CD4+ T cells have been shown to play a key role in disease progression, and their ability to infiltrate joints is associated with perpetuation of local and systemic inflammatory responses. A diverse range of T cell receptor (TCR) usage has been demonstrated in RA patients, however how such diversity arises and is shaped remains unclear. Understanding the development of CD4+ T cell antigen specific responses will therefore be important for the development and application of antigen-specific therapeutic tolerance regimes.

To investigate these antigen specific responses, CD4+ T cell clonality was examined using the OVA induced breach of tolerance model of experimental arthritis, allowing the assessment of developing antigen specific responses in the early stages of arthritis. The initial articular CD4+ T cell response was found to be oligoclonal in nature, with enrichment of several TCRVβ families in the inflamed joint. Moreover, the enrichment for some families is associated with joint derived antigens. Next-generation sequencing analysis of CDR3β sequences of CD4+ T cell clones revealed the dynamics of clonal responses between the inflamed joint and its associated draining lymph node and how these responses change with the progression of the disease. Inflamed joints displayed similar CD4+ T cell repertoire diversity at early and late stages of the disease, while inflamed lymph nodes displayed increased repertoire diversity with disease progression. Moreover, the number of CD4+ T cell clones shared between the inflamed joint and lymph node decreased with time. However, correlation analyses of highly abundant clones between inflamed joints and lymph nodes suggested continued migration of CD4+ T cell clones from inflamed lymph nodes to the joints. The decreased diversity in inflamed lymph nodes at the later time point may be a reflection of epitope spreading to the initial inciting antigen as well as development of new responses to neo antigens released as a result of continued joint damage. The hypothesis is that the reduced CD4+ T cell diversity in the inflamed lymph nodes will eventually be mirrored in the joint if the disease continues untreated.

This research provides insight on the dynamics of the antigen specific response between the inflamed tissue and its draining lymph node with disease progression, highlighting important site specific and temporal differences in clonal diversity with disease development and also highlights the role autoreactive CD4+ T cell responses play in disease progression. By understating the evolution of CD4+ T cell responses in RA, more informed decisions can be made on how antigen-specific therapeutics should be applied and will help develop more effective regimes to reinstate self-tolerance, with the ultimate goal of moving towards drug free remission and a cure.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Immunology, inflammation, rheumatoid arthritis.
Subjects: Q Science > QR Microbiology > QR180 Immunology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Immunology
Supervisor's Name: Garside, Professor Paul
Date of Award: 2020
Depositing User: Shaima Mazin Jawad Al Khabouri
Unique ID: glathesis:2020-80243
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 09 Mar 2020 12:42
Last Modified: 11 Mar 2020 12:43
URI: http://theses.gla.ac.uk/id/eprint/80243
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