CD25+CD4+ regulatory T cells in rheumatic disease

CD25+CD4+ T cells represent a unique cell lineage of thymus derived naturally occurring regulatory T cells. The gene Foxp3 (mouse)/ FOXP3(human) is strictly related to their generation in the thymus and their regulatory function in the periphery. In mice, these Foxp3+CD25+CD4+ regulatory T cells have proven to control autoimmunity and various inflammatory immune reactions by suppressing autoreactive and effector T cell responses.

In this thesis, the role of CD25+CD4+ regulatory T cells in patients with rheumatic disease was investigated. A spectrum of inflammatory joint diseases was studied, ranging from single joint inflammation to systemic rheumatic disease, including rheumatoid arthritis (RA), an autoimmune disease. Synovial fluid containing inflammatory cells was obtained from the joint of these patients. The isolated CD25+CD4+ T cells expressed high levels of FOXP3 and were able to suppress both proliferation and cytokine production of other CD4+ T cells in vitro. In addition, these FOXP3+CD25+CD4+ regulatory T cells were enriched in the inflamed joint as compared to the peripheral blood, and lower in peripheral blood of patients as compared to healthy individuals.

These data suggest an active accumulation of regulatory T cells at the site of inflammation. The increase in frequency and the suppressive function of these FOXP3+CD25+CD4+ regulatory T cells were observed in all inflamed joints, irrespective of diagnosis, disease duration or disease activity. FOXP3 message was also detected in the inflamed synovial tissue of patients, suggesting the presence of these regulatory T cells in the target tissue as well.

In summary, our data suggest that the immune system is actively trying to control the ongoing inflammation by recruiting FOXP3+CD25+CD4+ regulatory T cells to the joint. To which extent these cells are able to perform their suppressive function in vivo is not yet clarified, different possibilities are discussed in this thesis. The work in this thesis provides a basis for future research on regulatory T cells and their potential therapeutic use in rheumatic diseases.

List of scientific papers

I. Cao D, Malmstrom V, Baecher-Allan C, Hafler D, Klareskog L, Trollmo C (2003). Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol. 33(1): 215-23.
https://doi.org/10.1002/immu.200390024

II. Cao D, van Vollenhoven R, Klareskog L, Trollmo C, Malmstrom V (2004). CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease. Arthritis Res Ther. 6(4): R335-46.
https://doi.org/10.1186/ar1192

III. Cao D, Brojesson, Larsson P, Rudin A, Klareskog L, Malmstrom V, Trollmo C (2005). FOXP3 identifies regulatory CD25brightCD4+ cells inrheumatic joint. [Submitted]

IV. Cao D, Ulfgren AK, Trollmo C, Malmström V (2005). Comparative analysis of FOXP3 in target organ and circulation of rheumatic patients. [Manuscript]