Suppression of humoral immune responses by FOXP3+ regulatory T cells and regulation of trafficking receptor expression in FOXP3+ T cells
Abstract
Regulatory T cells expressing FOXP3 in their nuclei are distinct T cells which can suppress proliferation of T cell and T cell mediated immune responses. In addition, trafficking receptors such as chemokine receptors and adhesion molecules regulate T cell migration to various organs. Currently, relative very little information is available about the migration to and function of regulatory T cells within the germinal centers (GCs). We found, in human tonsils, there is a regulatory T cell subset (CD4+CD25+CD69 -T cell) which suppresses GC-Th cell-dependent B cell immune responses. CD4+CD25+CD69-T cells express high levels of CCR7, the T cell zone chemokine receptor and low levels of CXCR5, the B cell zone chemokine receptor on their surface. They migrate well to CCL19, a T cell area chemokine, but poorly migrate to CXCL13, the B cell area chemokine. Upon activation, CD4+CD25+CD69 -T cells acquire migratory capacity toward GCs by down-regulating CCR7 and up-regulating CXCR5. Our in vitro study showed that CD4+CD25 +CD69-T cells suppress GC-Th cells and GC-Th cell-driven B cell immune responses such as immunoglobulin production, survival and expression of activation-induced cytosine deaminase. Additionally, regulatory T cells can also directly suppress B cell immune responses without initially having to suppress T cells. To understand their trafficking potential in the blood circulation, we examined the regulation of trafficking receptor expression on human FOXP3+ T cells in human circulation. We found that there are two different types of FOXP3+ T cells (naïve vs memory) in neonatal blood, adult blood and tonsils. Naïve FOXP3 + T cells mainly express lymphoid tissue homing receptors, while memory FOXP3+ T cells highly express Th1/Th2-associated trafficking receptors. During activation and differentiation, the naïve, naïve FOXP3+ T cells begin to up-regulate Th1/Th2-associated trafficking receptors, demonstrating the chemokine receptor switch from naive to memory type. Our results have identified a subset of Tregs and a potential regulation mechanism for the trafficking of these Tregs to GCs. These results establish also the differentiation-dependent trafficking receptor change in human FOXP3 + T cells, which is probably important for their effective distribution in the body for suppression of effector T cells and immune tolerance.
Degree
Ph.D.
Advisors
Kim, Purdue University.
Subject Area
Biology|Cellular biology|Immunology
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