Background/Purpose:   Decreased numbers or altered functions of regulatory T cells (Tregs) have been reported in many inflammatory rheumatic diseases, and Tregs are considered promising therapeutic targets for autoimmune diseases. It is thus of high importance to delineate the pathways controlling Tregs biology and the onset of autoimmunity. Fos-related antigen 2 (Fra2) is a transcription factor belonging to the Fos family proteins which is part of the AP-1 transcription complex. Our aim is to characterize the potential role of Fra2 in controlling Tregs and autoimmunity.

Methods:   Fra2 transgenic (tg) mice were generated, in which the Fra2 transcription factor is ubiquitously overexpressed. T lymphocyte populations were analyzed by flow cytometry, and pathological manifestations in multiple organs by histology. Bone marrow cells were transferred into lethally irradiated recipients to create Fra2-wt chimeric mice. Purified CD4 T cells were transferred into Rag2^-/-mice lacking T and B cells.

Results:   At 3 weeks of age, Fra2 mice showed a striking decrease of the Treg population (CD4⁺CD25⁺FoxP3⁺ in wt and Fra2 littermates spleens: 11.35 and 5.75% of CD4⁺, respectively, p=0.0005, n=6). The strong decrease in Tregs was stable over time and also observed in CD4⁺ single positive thymocytes, indicating that Fra2 mice have a defect in natural Treg development. Interestingly, from 7 weeks on, we could also detect the appearance of activated T cells (CD4⁺ and CD8⁺, with CD62L^highCD44^highCD127^lowprofile) which represented up to 60% of total T cells by 16 weeks of age. While the phenotype of young mice was limited to decreased Tregs, macroscopic and histological observations in 16 week-old mice showed the presence of an extensive multi-organ autoimmune phenotype: Perivascular inflammatory infiltrates, containing T cells, B cells and numerous granulocytes were observed in the lung and liver with fibrosis and vasculopthy. Extensive inflammation and fibrosis were observed in the thymus. Spleens were also enlarged with pronounced extramedullary haematopoiesis. Fra2 tg mice also developed dermatitis on eyelids and back-skin, with an increase in dermal and epidermal thickness. Finally, duodenum was enlarged due to acute inflammation and reactive hyperplasia. To understand whether the effect of Fra2 is T cell intrinsic or extrinsic, we also performed bone marrow transfer experiments in which irradiated wt recipient mice received Fra2 tg bone marrow. Interestingly, chimera mice displayed a decreased percentage of Tregs confirming an intrinsic role of Fra2 in Treg development. Finally we could show that transfer of purified CD4 T cells from Fra2 tg mice into lymphopenic host (Rag2^-/-) was sufficient to transfer the phenotype, demonstrating the ability of CD4 T cells to induce the phenotype.

Conclusion:   These data suggest that Fra2 overexpression inhibits natural Treg development, resulting in 1: diminished Tregs, 2: activation of effector T cells and 3:development of inflammation in multiple organs. This is the first evidence for a role of Fra2 in controlling Treg development and autoimmunity. This murine model also provides a unique opportunity to delineate the function of the Fra2 pathway in T cells and Tregs and its impact on autoimmunity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-transcription-factor-fra2-is-playing-a-key-role-in-treg-development-and-autoimmunity/