Dependence of Self-Tolerance on TRAF6-Directed Development of Thymic Stroma

Abstract

The microenvironments of the thymus are generated by thymic epithelial cells (TECs) and are essential for inducing immune self-tolerance or developing T cells. However, the molecular mechanisms that underlie the differentiation of TECs and thymic compartmentalization are not fully understood. Here we show that deficiency in the tumor necrosis factor receptor-associated factor (TRAF) 6 results in disorganized distribution of medullary TECs (mTECs) and the absence of mature mTECs. Engraftment of thymic stroma of TRAF6(-/-) embryos into athymic nude mice induced autoimmunity. Thus, TRAF6 directs the development of thymic stroma and represents a critical point of regulation for self-tolerance and autoimmunity.

Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance

“…Nonetheless, we observed a quantitative difference in the expression of a particular MHC II/p complex, I-Eα (52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68) bound to I-A b molecule in Atg5 -/-cTEC ( Figure 3). To our knowledge, this is the first study showing changes in the MHCII/p repertoire in autophagy deficient APC in an in vivo system.…”

“…Studies on mice with impaired development and/or organization of the medulla revealed its crucial role in tolerance induction. Thus, in Rel-B, lymphotoxin-β receptor and TRAF6 deficient mice the medullary compartment is altered, which results in the development of autoimmunity [57][58]59 . Furthermore, inhibition of thymocyte homing to the medulla in CCR7 and CCR7L deficient mice results in the break-down of central tolerance 60 .…”

“…Once in the cytosol, the polypeptides can gain access to the MHC class I loading route after proteasomal processing and TAP-mediated translocation to the ER. However, the studies relying on the specific inhibition of proteasomal activity and/or TAP function in the phenomenon of "cross-presentation" should be carefully interpreted, findings that a specific I-A b /I-Eα (52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68) epitope is expressed at a lower level in cTEC then in DC [122][123][124] . The observations that indicate involvement of a similar set of proteases involved in antigen processing in the cell types mediating tolerance induction, i.e., mTEC and DC, and peripheral APC are intuitively understandable.…”

Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance

“…However, the precise qualitative and quantitative contribution of individual thymic stromal cell subsets to distinct modes of central T cell tolerance, for instance, negative selection versus deviation into the Foxp3 + regulatory T (T reg ) cell lineage, has not been clarified. [5][6][7][8][9][10] . However, the interpretation of these observations remains complex because perturbations of mTEC differentiation do not only affect their bona fide APC function, but may also disrupt the three-dimensional organization of the medulla and diminish the phenomenon of 'promiscuous' expression of peripheral tissue-antigens (PTAs).…”

The complicated role of NF-κB in T-cell selection

“…32 Consistently, mice with severe defects of thymic medulla, such as Relb 2/2 , aly/aly and Traf6 2/2 mice, all have dramatically reduced numbers of Foxp3 1 nTregs in thymi (our unpublished finding). 13,15 The underlying mechanism for thymic medulla to control Foxp3 1 nTreg development is still vastly unknown; however, several possibilities exist: firstly, TRAs could be one of the signals provided by the medulla for nTreg development. A recent study has demonstrated that TRA-specific Tregs can be selected by Aire 1 mTECs, while the cross-presentation by thymic DCs is not required.…”