Functions of regulatory T cells in regulation of immunity and immune tolerance.

摘要

FoxP3+ regulatory T cells (Tregs) are known as an immune suppressor and play important roles in immune tolerance and homeostasis. Regulation of Tregs is critical for maintenance of immune responses such as inflammation and infection. Therefore, Tregs should be regulated by effective ways during immune responses. Control of generation, migration and function of Tregs would be important to achieve for proper function of Tregs. (Chapter 1) We examined the migratory capacity, particularly regulation of trafficking receptor expression, of FoxP3+ T cells. We found that FoxP3+ regulatory T cells undergo the first chemokine receptor switch in the thymus for generation of CCR7+CXCR4lowCD62L+FoxP3 + cells. Thymus-generated FoxP3+ T cells mainly migrated to secondary lymphoid tissues. After antigen priming in the lymph nodes, activated FoxP3+ T cells expressed effector/memory/inflammation-associated trafficking receptors, but lost expression of CD62L. In conclusion of this chapter, FoxP3+ T cells have an accelerated chemokine receptor switch for migration from secondary lymphoid tissues to non-lymphoid tissues, compared to FoxP3- T cells. (Chapter 2) We next studied regulation of FoxP3+ T cells on production of myeloid cells. We found that FoxP3-deficient mice or Treg-depleted mice have enhanced myelopoiesis in the spleen, but not in the marrow. Myelopoietic cytokines such as GM-CSF and IL-3, produced by effector CD4+ T cells, caused increased extramedullary myelopoiesis. Natural or induced FoxP3+ T cells were efficient in suppressing splenic myelopoiesis in response to antigenic stimulation. Suppression of myelopoiesis by FoxP3+ T cells was dependent on cell contact, but not TGFbeta signaling. In these studies, we concluded that FoxP3+ regulatory T cells negatively regulated splenic extramedullary myelopoiesis, induced upon antigenic activation or in systemic inflammation, by suppression of myelopoietic cytokine-producing T cells. (Chapter 3) We studied how Tregs are induced in the periphery. It has been reported that Tregs were increased during pregnancy to protect fetus from maternal immunity. Progesterone (P4) is one of female sex hormones, which is produced at a high concentration during pregnancy. Therefore, we investigated the effect of P4 on Treg cells and found that P4 was able to induce highly suppressive FoxP3+ T cells from human cord blood (CB) naive T cells, but not adult peripheral blood (PB) T cells. Compared to TGFbeta1-induced Tregs, P4-induced Tregs expressed the memory-type-associated antigens. Consistently, CB CD4+ T cells are enriched with memory-type FoxP3 + T cells. In addition, P4 inhibited the generation of Th17 cells. P4 increased STAT5 activation in response to IL-2, while it decreased STAT3 activation by IL-6. IL-6 is a key molecule that modulated T cell differentiation (Treg versus Th17) and P4 reduced the expression of IL-6 receptor in T cells. The results in chapter 3 demonstrated that P4 was efficiently able to induce FoxP3+ T cells for promotion of immune tolerance. Taken together, these studies established the development of migration activity, functions in regulation of myelopoiesis, and generation of induced Tregs for normal formation of immune tolerance.