TNF superfamily members play distinct roles in shaping the thymic stromal microenvironment

Bichele, Rudolf; Kisand, Kai; Peterson, Pärt; Laan, Martti

doi:10.1016/j.molimm.2016.02.015

Cited by 18 publications

(18 citation statements)

References 40 publications

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“…1B). The TNF-induced genes Cxcl2, Cxcl9, and Ccl5, which serve as chemoattractants for hematopoietic progenitors to the thymus or for T cell emigration (21) were upregulated in cTECs from Psmb11 2/2 mice (Fig. 1C).…”

Section: Psmb11 Regulates Genes Involved In Chemokine Signaling and Cmentioning

confidence: 99%

PSMB11 Orchestrates the Development of CD4 and CD8 Thymocytes via Regulation of Gene Expression in Cortical Thymic Epithelial Cells

Apavaloaei

Brochu

Dong

et al. 2019

The Journal of Immunology

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T cell development depends on sequential interactions of thymocytes with cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells. PSMB11 is a catalytic proteasomal subunit present exclusively in cTECs. Because proteasomes regulate transcriptional activity, we asked whether PSMB11 might affect gene expression in cTECs. We report that PSMB11 regulates the expression of 850 cTEC genes that modulate lymphostromal interactions primarily via the WNT signaling pathway. cTECs from Psmb11−/− mice 1) acquire features of medullary thymic epithelial cells and 2) retain CD8 thymocytes in the thymic cortex, thereby impairing phase 2 of positive selection, 3) perturbing CD8 T cell development, and 4) causing dramatic oxidative stress leading to apoptosis of CD8 thymocytes. Deletion of Psmb11 also causes major oxidative stress in CD4 thymocytes. However, CD4 thymocytes do not undergo apoptosis because, unlike CD8 thymocytes, they upregulate expression of chaperones and inhibitors of apoptosis. We conclude that PSMB11 has pervasive effects on both CD4 and CD8 thymocytes via regulation of gene expression in cTECs.

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Section: Psmb11 Regulates Genes Involved In Chemokine Signaling and Cmentioning

confidence: 99%

PSMB11 Orchestrates the Development of CD4 and CD8 Thymocytes via Regulation of Gene Expression in Cortical Thymic Epithelial Cells

Apavaloaei

Brochu

Dong

et al. 2019

The Journal of Immunology

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“…While the interactions between cortical thymic epithelial cells (cTECs) and thymocytes are responsible for TCR‐mediated positive selection, the medullary thymic epithelial cells (mTECs) and dendritic cells (DCs) express and present self‐antigens and co‐stimulatory molecules to the developing thymocytes and play a central role in negative selection and the induction of central tolerance. In addition, it has been shown that TECs and fibroblasts produce many soluble factors and transmembrane proteins such as IL‐7, Kitl, and Dll4 that are essential for thymocyte proliferation, differentiation, and survival whereas thymocyte‐produced factors such as RANKL, CD40, and LTβ are critical for the proper differentiation of TECs . Thus, it is well established that bidirectional crosstalk is required for the proper function of both lymphoid as well as nonlymphoid thymic cells.…”

Section: Introductionmentioning

confidence: 99%

Pregnancy‐induced thymic involution is associated with suppression of chemokines essential for T‐lymphoid progenitor homing

et al. 2016

Self Cite

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During normal pregnancy, the thymus undergoes a severe reduction in size and thymocyte output, which may contribute to maternal-fetal tolerance. It is presently unknown whether the pregnancy-induced thymic involution also affects nonlymphoid thymic cell populations and whether these changes in stromal cells play a role in the reduction in thymocyte numbers. Here, we characterize the changes in thymic lymphoid and nonlymphoid cells and show that pregnancy results in a reduction of all major thymic lymphoid cell populations, including the early T-lymphoid progenitors (TLPs) and thymic regulatory T cells. In addition to the thymocytes, the thymic involution also includes all major nonlymphoid cell populations, which show a profound reduction in cell numbers. We also show that during pregnancy, the thymic nonlymphoid cells exhibit decreased expression of chemokines that are essential for TLP homing: CCL25, CXCL12, CCL21, and CCL19. In addition, the expression of these chemokines was substantially downregulated by shortterm treatment with progesterone but not estrogen. Collectively, these findings suggest a novel mechanism for the pregnancy-induced reduction in TLP homing and the resulting thymic involution. Keywords:Chemokines r Homing r Pregnancy r Thymus r Tolerance r T-lymphoid progenitor Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe developing fetus expresses paternal antigens and, therefore, should be rejected by the maternal immune system [1][2][3]. However, during normal pregnancy, the accompanying changes in the maternal immune system allow the semiallogenic fetus to be tolerated. Accordingly, insufficient immune modulation and a failure of tolerance induction to the developing fetus have been linked to Correspondence: Dr. Martti Laan e-mail: martti.laan@ut.ee several severe pregnancy complications, such as preeclampsia and recurrent spontaneous abortions [4][5][6].A well-documented feature of pregnancy-induced immune adaptation is the acute and transient reduction in thymus size [7,8]. This pregnancy-induced thymic involution has been found in all mammalian species examined [9] and, at least in the mouse, is required for successful implantation and normal fertility [10]. Most of the characterized mechanisms thought to underlie this * These authors contributed equally to this study.www.eji-journal.eu Eur. J. Immunol. 2016. 46: 2008-2017 Immunomodulation and immune therapies 2009 involution have been focused on pregnancy-related increases in certain steroid hormones and their effects on different thymocyte populations. For example, it has been shown that progesterone signaling is needed for thymic involution in pregnancy and this effect is related to a developmental block of thymocyte differentiation at the double negative (DN)1 stage [10]. Another study indicated that the pregnancy-induced increase in the estrogen level is responsible for diminished proliferation of virtually all thymocyte populations without affecting their a...

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“…The NFκB pathway plays a vital role in mTEC development and consequently in the establishment of central tolerance (Akiyama et al, 2005; Burkly et al, 1995; Kajiura et al, 2004). Recent studies using transcriptomics and functional assays have led to more clarity on how the several NFκB ligands, through which thymic crosstalk occurs, function during mTEC maturation (Akiyama et al, 2016; Bichele et al, 2016; Desanti et al, 2012; Mouri et al, 2011). In particular, Akiyama and colleagues identified two separable UEA1 + mTEC progenitor stages, pro-pMECs and pMECs based on the expression of RANK, MHCII and CD24 (Akiyama et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Canonical NOTCH signaling controls the early progenitor state and emergence of the medullary epithelial lineage in fetal thymus development

et al. 2019

Preprint

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Thymus function depends on the epithelial compartment of the thymic stroma. Cortical thymic epithelial cells (cTECs) regulate T cell lineage commitment and positive selection, while medullary (m) TECs impose central tolerance on the T cell repertoire. During thymus organogenesis, these functionally distinct sub-lineages are thought to arise from a common thymic epithelial progenitor cell (TEPC). The mechanisms controlling cTEC and mTEC production from the common TEPC are not however understood. Here, we show that emergence of the earliest mTEC lineage-restricted progenitors requires active NOTCH signaling in progenitor TEC and that, once specified, further mTEC development is NOTCHindependent. In addition, we demonstrate that persistent NOTCH activity favors maintenance of undifferentiated TEPC at the expense of cTEC differentiation. Finally, we uncover a direct interaction between NOTCH and FOXN1, the master regulator of TEC differentiation. These data establish NOTCH as a potent regulator of TEPC and mTEC fate during fetal thymus development and are thus of high relevance to strategies aimed at generating/regenerating functional thymic tissue in vitro and in vivo.

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TNF superfamily members play distinct roles in shaping the thymic stromal microenvironment

Cited by 18 publications

References 40 publications

PSMB11 Orchestrates the Development of CD4 and CD8 Thymocytes via Regulation of Gene Expression in Cortical Thymic Epithelial Cells

PSMB11 Orchestrates the Development of CD4 and CD8 Thymocytes via Regulation of Gene Expression in Cortical Thymic Epithelial Cells

Pregnancy‐induced thymic involution is associated with suppression of chemokines essential for T‐lymphoid progenitor homing

Canonical NOTCH signaling controls the early progenitor state and emergence of the medullary epithelial lineage in fetal thymus development

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