Decreased frequencies of CD4⁺CD25⁺Foxp3⁺ cells and the potent CD103⁺ subset in peripheral lymph nodes correlate with autoimmune disease predisposition in some strains of mice

Abstract

The CD4⁺CD25⁺Foxp3⁺ cells are essential for regulation of the immune response, and the integrin, CD103 (α_Eβ₇), identifies a potent subset of these cells. Defects in CD4⁺CD25⁺Foxp3⁺ cells are thought to contribute to susceptibility to autoimmune disease in predisposed individuals. Studies evaluating the quality and quantity of CD4⁺CD25⁺Foxp3⁺ regulatory cell populations in the context of autoimmune disease susceptibility have been inconclusive, and few if any, have analyzed the CD103 subset. In this study, we analyzed regulatory T cells (Tregs) from different strains of mice with varying degrees of susceptibility to autoimmune disease. We found no differences in the ability of CD4⁺CD25⁺ or the CD103⁺ subset of Tregs from young female (NZB × NZW)F1 (BWF1), SJL, C57BL/6, or BALB/c mice to suppress CD4⁺CD25⁻ responders in vitro. Analysis of CD4⁺Foxp3⁺ and CD4⁺CD25⁺CD103⁺ cell frequencies in lymphoid organs revealed that BWF1 mice had dramatically lower percentages of both populations in the lymph node (LN) than the other strains, and lower percentages in the spleen in all but the C57BL/6 strain. We next determined whether these findings extended to another autoimmune-prone strain. Similar to BWF1 mice, percentages of CD4⁺Foxp3⁺ and CD4⁺CD25⁺CD103⁺ cells were significantly lower in predisease NOD mice. The low frequencies of CD4⁺Foxp3⁺ and CD4⁺CD25⁺CD103⁺ cells in BWF1 and NOD mice were not due to deficiencies in either thymic production or homeostatic proliferation. These data indicate that decreased percentages of CD4⁺Foxp3⁺ cells and particularly, CD4⁺CD25⁺CD103⁺ cells in LN correlate with the predisposition to spontaneous development of autoimmune disease.

Keywords::

• Tregs
• autoimmune disease
• mice
• CD103
• Foxp3

Acknowledgments

We would like to thank Barry Uldis, Mike Tanner, and Thomas Miller at the Institute for Cellular Therapeutics for their help with cell sorting and FACS^® analysis.

Declaration of interest. This work was supported by grants from the National Institute of Health (R21AI51870 and R01AI064421) and the Lupus Research Institute. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.