- Characterising the autoantigen-specific CD4+ T cell response and repertoire over the course of antigen-induced arthritis in a mouse model
Awards
Author(s):
Category:
Institution:
Region:
Winner Category:
Year:
Abstract:
- Rheumatoid arthritis (RA) is an autoimmune disease where humoral and cellular immunities against multiple self-antigens are implicated in pathogenesis. Autoantigen-specific CD4+ T cells have been detected in RA patients, and a biased T cell receptor (TCR) repertoire has been reported in the joints of recent-onset RA patients suggesting T cell expansion. Furthermore, studies in collagen-induced arthritis mouse models have shown clonal expansion of particular TCR-expressing CD4+ T cells at disease onset. However, it remains to be elucidated how the autoantigen-specific CD4+ T cell response and TCR repertoire develops during the prodrome and after disease onset. To address this question an antigen-induced arthritis model was used, where immunity to recombinant human aggrecan G1 proteoglycan in BALB/c mice was induced with a prime and two booster injections (termed the PGIA model). This PGIA model recapitulates the clinical and immunological features of RA, with development of PG-specific antibodies as disease develops. Using MHC class II tetramers, phenotypic markers, and single-cell TCR sequencing, splenic aggrecan-specific CD4+ T cells were studied before and after onset of proteoglycan-induced arthritis. The number of splenic aggrecan-specific CD4+ T cells increased over time, coinciding with increased disease severity. Two weeks after priming, regulatory T cells decreased and effector memory T cells increased within the splenic aggrecan-specific CD4+ T cell population. The aggrecan-specific CD4+ TCR repertoire narrowed in the first weeks after priming, and was most focussed concomitant with a transient increase in disease activity. The aggrecan-specific TCR repertoire also showed preferential usage of TRBV13-1+, 13-2+ and 2+ TCRs across the time course, which appeared to be arthritogenic following SCID transfer. Public TRBV13+ clonotypes with conserved amino acid residues were also identified, suggesting these TCRs were antigen-selected. Interestingly, aggrecan-specific CD4+ T cells were very rarely detected in arthritic paws. These data suggest that in the disease prodrome, a limited number of splenic effector memory aggrecan-specific clonotypes expand as regulation decreases, and these expanded clonotypes are arthritogenic. These data have important implications for the timing and target of antigen-specific immunotherapy.
Attached Documents: