Background/Purpose: CD4⁺ T cells are important contributors to the pathogenesis of Rheumatoid Arthritis (RA). The presence of activated T cells in the inflamed synovium, strong associations with HLA-DR4, ptpn22, ctla4 and cd28 implicate their contribution, while the success of T cell targeted CTLA-4-Ig therapeutic provide more direct evidence. Yet it remains unclear when and where CD4⁺ T cells mediate this pathogenic effect and whether the specificity of the cells is important.

Methods: A variation of antigen-induced arthritis using ovalbumin (OVA) as the inciting challenge was used to model articular inflammation. Th1 polarised OVA specific fluorescent (DsRed) OT-II TcR transgenic T cells were adoptively transferred and expanded in vivo by challenge with OVA/CFA. This allowed subsequent analysis and tracking of antigen-specific T cells as they were recruited to the ankle joint following periarticular injection of heat aggregated OVA (HAO). Flow cytometry allowed phenotyping of cells recruited to the inflamed articular environment. The T cell receptor (TcR) diversity of infiltrating endogenous T cells was assessed by PCR of Vβ genes. Dynamic interactions of responding DsRed T cell populations with joint residing CD11c YFP dendritic cells were visualized using intravital multiphoton laser scanning microscopy.

Results: Low numbers of the inciting OVA specific CD4⁺ T cells could be found in the joint tissue. However, a large influx of endogenous CD4⁺ T cells of unknown antigen specificity was also found. In comparison with the CD4⁺ T cells in the draining lymph node, this recruited T cell population expressed surface activation markers, produced TNFa and IFNg upon ex vivo restimulation and exhibited a narrower range of T cell receptor Vb usage. In addition, intravital imaging of the inflamed joint revealed that a sub-population of this infiltrate demonstrated slower motility speeds and longer periods of contact with articular dendritic cells, while others rapidly migrated throughout the tissue.

Conclusion: We present data demonstrating that while the numbers of inciting antigen-specific T cells to the joint tissue is small, it is associated with a subsequent influx of a large endogenous population of unknown antigen specificity that had acquired the ability to secrete pro-inflammtory cytokines. Oligoclonal TcR Vβ gene expression by the CD4⁺ T cells in the inflamed joint suggests some degree of antigen-specificity in recruitment while intravital imaging reveals that some of this infiltrate exhibits behaviour consistent with recognition of cognate peptide-MHCII.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/characterising-the-specificity-function-and-behavior-of-cd4-t-cells-initiating-inflammation-in-a-murine-model-of-rheumatoid-arthritis/