A regulatory role for TGF-β signaling in the establishment and function of the thymic medulla (original) (raw)
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Transforming Growth Factor-beta signaling in αβ thymocytes promotes negative selection
Nature Communications, 2019
In the thymus, the T lymphocyte repertoire is purged of a substantial portion of highly self-reactive cells. This negative selection process relies on the strength of TCR-signaling in response to self-peptide-MHC complexes, both in the cortex and medulla regions. However, whether cytokine-signaling contributes to negative selection remains unclear. Here, we report that, in the absence of Transforming Growth Factor beta (TGF-β) signaling in thymocytes, negative selection is significantly impaired. Highly autoreactive thymocytes first escape cortical negative selection and acquire a Th1-like-phenotype. They express high levels of CXCR3, aberrantly accumulate at the cortico-medullary junction and subsequently fail to sustain AIRE expression in the medulla, escaping medullary negative selection. Highly autoreactive thymocytes undergo an atypical maturation program, substantially accumulate in the periphery and induce multiple organ-autoimmune-lesions. Thus, these findings reveal TGF-β i...
TRAF3 enforces the requirement for T cell cross-talk in thymic medullary epithelial development
Proceedings of the National Academy of Sciences, 2013
Induction of self-tolerance in developing T cells depends on medullary thymic epithelial cells (mTECs), whose development, in turn, requires signals from single-positive (SP) thymocytes. Thus, the absence of SP thymocytes in Tcra −/− mice results in a profound deficiency in mTECs. Here, we have probed the mechanism that underlies this requirement for cross-talk with thymocytes in medullary development. Previous studies have implicated nonclassical NF-κB as a pathway important in the development of mTECs, because mice lacking RelB, NIK, or IKKα, critical components of this pathway, have an almost complete absence of mTECs, with resulting autoimmune pathology. We therefore assessed the effect of selective deletion in TEC of TNF receptor-associated factor 3 (TRAF3), an inhibitor of nonclassical NF-κB signaling. Deletion of TRAF3 in thymic epithelial cells allowed RelB-dependent development of normal numbers of AIRE-expressing mTECs in the complete absence of SP thymocytes. Thus, mTEC development can occur in the absence of cross-talk with SP thymocytes, and signals provided by SP T cells are needed to overcome TRAF3-imposed arrest in mTEC development mediated by inhibition of nonclassical NF-κB. We further observed that TRAF3 deletion is also capable of overcoming all requirements for LTβR and CD40, which are otherwise necessary for mTEC development, but is not sufficient to overcome the requirement for RANKL, indicating a role for RANKL that is distinct from the signals provided by SP thymocytes. We conclude that TRAF3 plays a central role in regulation of mTEC development by imposing requirements for SP T cells and costimulation-mediated cross-talk in generation of the medullary compartment.
…, 1995
Early thymocytes undergo extensive proliferation after their entry into the thymus, but cellular interactions and cytokines regulating this intrathymic step remain t o be determined. We analyzed the effects of various T-cell growth factors and cellular interactions on in vitro proliferation of early CD2'CD3/TCR-CD4-CD8-(triple negative [TN]) human thymocytes. Freshly isolated TN cells were then assayed for their growth capacity after incubation with CD21,111-monoclonal antibody (MoAb), recombinant human interleukin-2 (IL-21. IL-7, and/or IL-4. These cells displayed significant proliferative responses with IL-4, IL-7, or CD2-MoAb+lL-2. The addition of recombinant transforming growth factor p (TGFPI or autologous irradiated CD3'CD8+CD4-cells t o TN cell cultures dramatically decreased their growth responses t o IL-2 and IL-7, whereas IL-4-induced proliferation was less RANSFORMING GROWTH factors P (TGFP) are multifunctional homodimeric proteins that belong to the structurally related polypeptides termed the TGF superfamily.',2 TGFPl is secreted by a variety of cell types, including B cells, T cells, macrophages, and platelets, predominantly or exclusively in a latent form. The in vivo mechanism that controls activation of this latent form has not yet been d e f i~~e d .~.~ The pleiotropic activities of TGFPl include regulation of cell proliferation and differentiation, control of tissue repair, promotion of angiogenesis, and modulation of inflammatory responses.'~2,s TGFPl has also been shown as a potent inhibitor of T-cell proliferation, both in interleukin-2 (IL-2)-and IL-4-derived response^.^" On some mature human T-cell subsets, TGFPl was also shown to enhance the proliferative responses of immobilized CD3 monoclonal antibody (MoAb)-stimulated T cells." Recently, TGFP from thymic epithelial cells was shown to play a role in murine T-cell maturation.'' However, the role of TGFPl on early human T-cell proliferation was not clearly determined. T-cell differentiation occurs in the thymus where bone marrow-derived prothymocytes develop into cells expressing TCWCD3, a prerequisite event for their subsequent selection and function.14"* The first human intrathymic step is characterized by an extensive growth of early prec~rsors,'"'~ whereas the role of soluble growth factors T From the Molecular Immuno
Journal of Biological Chemistry, 2006
Medullary thymic epithelial cells function as antigen-presenting cells in negative selection of selfreactive T cell clones, a process essential for the establishment of central self-tolerance. These cells mirror peripheral tissues through promiscuous expression of a diverse set of tissue-restricted selfantigens. The genes and signaling pathways that regulate the development of medullary thymic epithelial cells are not fully understood. Here we show that mice deficient in NF-κB2, a member of the NF-κB family, display a marked reduction in the number of mature medullary thymic epithelial cells that express CD80 and bind the lectin Ulex europaeus agglutinin-1, leading to a significant decrease in the extent of promiscuous gene expression in the thymus of NF-κB2 −/− mice. Moreover, NF-κB2 −/− mice manifest autoimmunity characterized by multiorgan infiltration of activated T cells and high levels of autoantibodies to multiple organs. A subpopulation of the mice also develops immune-complex glomerulonephritis. These findings identify a physiological function of NF-κB2 in the development of medullary thymic epithelial cells and, thus, the control of self-tolerance induction.
Journal of Biological Chemistry, 2006
Medullary thymic epithelial cells function as antigen-presenting cells in negative selection of self-reactive T cell clones, a process essential for the establishment of central self-tolerance. These cells mirror peripheral tissues through promiscuous expression of a diverse set of tissue-restricted self-antigens. The genes and signaling pathways that regulate the development of medullary thymic epithelial cells are not fully understood. Here we show that mice deficient in NF-B2, a member of the NF-B family, display a marked reduction in the number of mature medullary thymic epithelial cells that express CD80 and bind the lectin Ulex europaeus agglutinin-1, leading to a significant decrease in the extent of promiscuous gene expression in the thymus of NF-B2 ؊/؊ mice. Moreover, NF-B2 ؊/؊ mice manifest autoimmunity characterized by multiorgan infiltration of activated T cells and high levels of autoantibodies to multiple organs. A subpopulation of the mice also develops immune complex glomerulonephritis. These findings identify a physiological function of NF-B2 in the development of medullary thymic epithelial cells and, thus, the control of self-tolerance induction.
The Journal of Immunology, 2010
The thymic medulla represents a key site for the induction of T cell tolerance. In particular, autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) provide a spectrum of tissue-restricted Ags that, through both direct presentation and cross-presentation by dendritic cells, purge the developing T cell repertoire of autoimmune specificities. Despite this role, the mechanisms of Aire+ mTEC development remain unclear, particularly those stages that occur post-Aire expression and represent mTEC terminal differentiation. In this study, in mouse thymus, we analyze late-stage mTEC development in relation to the timing and requirements for Aire and involucrin expression, the latter a marker of terminally differentiated epithelium including Hassall’s corpuscles. We show that Aire expression and terminal differentiation within the mTEC lineage are temporally separable events that are controlled by distinct mechanisms. We find that whereas mature thymocytes are not e...
Cytokine crosstalk for thymic medulla formation
Current Opinion in Immunology, 2011
The medullary microenvironment of the thymus plays a crucial role in the establishment of self-tolerance through the deletion of self-reactive thymocytes and the generation of regulatory T cells. Crosstalk or bidirectional signal exchanges between developing thymocytes and medullary thymic epithelial cells (mTECs) contribute to the formation of the thymic medulla. Recent studies have identified the molecules that mediate thymic crosstalk. Tumor necrosis factor superfamily cytokines, including RANKL, CD40L, and lymphotoxin, produced by positively selected thymocytes and lymphoid tissue inducer cells promote the proliferation and differentiation of mTECs. In return, CCR7 ligand chemokines produced by mTECs facilitate the migration of positively selected thymocytes to the medulla. The cytokine crosstalk between developing thymocytes and mTECs nurtures the formation of the thymic medulla and thereby regulates the establishment of self-tolerance.
Developmental immunology, 2000
TNF, lymphotoxin (LT) and their receptors are expressed constitutively in the thymus. It remains unclear whether these cytokines play a role in normal thymic structure or function. We have investigated thymocyte differentiation, selection and thymic organogenesis in gene targeted mice lacking LTalpha, TNF, or both (TNF/LTalpha-/-). The thymus was normal in TNF/LTalpha-/- mice with regard to cell yields and stromal architecture. Detailed analysis of alphabeta and gammadelta T cell-lineage thymocyte subsets revealed no abnormalities, implying that neither TNF nor LT play an essential role in T cell differentiation or positive selection. The number and distribution of thymic CD11c+ dendritic cells was also normal in the absence of both TNF and LTalpha. A three-fold increase in B cell numbers was observed consistently in the TNF/LTalpha-/- thymus. This phenotype was due entirely to the LTalpha deficiency and associated with changes in the hemopoietic compartment, rather than the thymic ...