Stat3 Signaling Promotes Survival And Maintenance Of Medullary Thymic Epithelial Cells.
Stat3 Signaling Promotes Survival And Maintenance Of Medullary Thymic Epithelial Cells.
复制标题
DOI：
10.1371/journal.pgen.1005777
复制
发表时间：
2016-01
期刊：
影响因子：
4.5
通讯作者：
Richie ER
中科院分区：
文献类型：
--
作者：
Lomada D;Jain M;Bolner M;Reeh KA;Kang R;Reddy MC;DiGiovanni J;Richie ER
Medullary thymic epithelial cells (mTECs) are essential for establishing central tolerance by expressing a diverse array of self-peptides that delete autoreactive thymocytes and/or divert thymocytes into the regulatory T cell lineage. Activation of the NFκB signaling pathway in mTEC precursors is indispensable for mTEC maturation and proliferation resulting in proper medullary region formation. Here we show that the Stat3-mediated signaling pathway also plays a key role in mTEC development and homeostasis. Expression of a constitutively active Stat3 transgene targeted to the mTEC compartment increases mTEC cellularity and bypasses the requirement for signals from positively selected thymocytes to drive medullary region formation. Conversely, conditional deletion of Stat3 disrupts medullary region architecture and reduces the number of mTECs. Stat3 signaling does not affect mTEC proliferation, but rather promotes survival of immature MHCIIloCD80lo mTEC precursors. In contrast to striking alterations in the mTEC compartment, neither enforced expression nor deletion of Stat3 affects cTEC cellularity or organization. These results demonstrate that in addition to the NFkB pathway, Stat3-mediated signals play an essential role in regulating mTEC cellularity and medullary region homeostasis. T cells, an essential component of the immune system, generate protective immune responses against pathogenic organisms and cancer cells. T cells are produced in the thymus, which provides a unique microenvironment required for T cell development. Distinct subsets of thymic epithelial cells (TECs) in the outer cortex and inner medulla provide signals required for the survival and differentiation of immature T cells, referred to as thymocytes. Medullary TECs (mTECs) play a critical role in preventing autoimmunity because they have the unique ability to express peptides found in other organs throughout the body. Presentation of self-peptides to thymocytes causes deletion of cells that express high affinity self-reactive receptors. Numerous studies have established that a major signaling pathway mediated by NFκB family members is indispensable for mTEC development. However, whether other signaling pathways are also required has remained an open question. Here, we use gain- and loss-of-function genetic approaches to demonstrate that another pathway, mediated by Stat3 signaling, plays an important role in mTEC development and homeostasis. We show that constitutive Stat3 activation enhances the survival of immature mTECs and bypasses the requirement for thymocyte-derived signals in medullary region formation. In contrast, Stat3 depletion reduces mTEC cellularity and impairs medullary region formation.
