Background/Purpose: T cells orchestrate joint inflammation in rheumatoid arthritis (RA), yet they are difficult to study due to the small numbers of antigen-specific cells. The goal of this study was to characterize the phenotypic and functional changes that occur in autoimmune T cells following the induction of pathological events in a humanized model of arthritis.

Methods: We developed a double transgenic mouse containing both the HLA-DR1 transgene and an HLA-DR1-restricted CII (263–273)-specific TCR in order to more closely mimic the human immune responses that occur in RA.

Results: In vitro, CII-specific T cells demonstrated an increased ability to proliferate in response to the CII immunodominant peptide and the cells altered their phenotype to become predominately CD62L^low and CD44^high “activated” T cells.  Functionally, the CII-specific T cells produced increased levels of Th1, Th2, and Th17-type cytokines in comparison to controls from HLA-DR1 single transgenic animals, when challenged with CII peptide.  Following immunization with CII/CFA, these mice develop an accelerated arthritis compared to single transgenic HLA-DR1 mice.  Histology confirmed that the double transgenic mice had greater pannus formation and cartilage destruction when compared to arthritic DR1 mice.  On the other hand, when the mice were treated orally with the analog peptide A12, the arthritis was significantly suppressed, despite the fact that >90% of the CD4+ T cells express the TCR Tg.   In the A12-treated mice, IL-2, IFN-γ, and IL-17 production dropped and high levels of IL-10 and IL-4 were produced.  

Conclusion: These data suggest that the model will be useful to study T cell directed therapies as well as the mechanisms of autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/characterization-of-t-cell-phenotype-and-function-in-a-double-transgenic-collagen-specific-tcr-hla-dr1-humanized-model-of-arthritis/