Regulation of Interleukin 4 Expression in T Cells by Mesenchymal Stem Cells

초록

Mesenchymal stem/stromal cells (MSCs) possess immunosuppressive properties, making them a potential alternative for cell therapy in immunological-related diseases such as graft vs. host disease, lupus, asthma, and atopic dermatitis (AD). Due to its increasing prevalence, AD has become a significant public health problem, and there is a need for alternative therapeutic options. Recently, preclinical and clinical studies of MSCs have shown a promising approach to treating AD. Our previous studies have shown that MSCs can be used for AD treatment due to their ability to suppress T and B cells. Using the MSC and lymphocyte co-culture system, we demonstrated that nitric oxide (NO) secreted by MSCs is the primary immunosuppressive factor for Th1 cells, particularly inhibiting IFN-?. MSCs can also inhibit Th2 cytokines, such as IL-4. However, which factor(s) from MSCs regulate IL-4 expression is still unknown. In our study, we stimulated T cells via soluble anti-CD3, which induces weak TCR stimulation, or plate-bound anti-CD3, which induces prolonged strong TCR stimulation. Consistent with our previous findings, MSCs demonstrated the ability to inhibit IL-4 expression under both stimulation systems. A particularly intriguing observation was that MSC-mediated IL-4 inhibition was only rescued by the NO inhibitor L-NMMA when plate-bound anti-CD3 antibodies stimulated T cells. In the case of stimulation with a soluble anti-CD3 system, MSC-mediated IL-4 inhibition remained unaffected by the NO inhibitor despite similar NO concentrations in both systems. This suggests that the mechanisms of MSC-mediated IL-4 suppression might vary depending on TCR strengths. Unraveling these mechanisms could provide a key to understanding the therapeutic efficacy of MSCs on AD. However, why IL-4 expression is rescued by NO inhibitors under specific TCR strength conditions remains unknown. This intriguing question will be the focus of our future studies.