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

Abstract

The nuclear factor (NF)-kB transcription factor family plays important roles in the immune system. Aberrant NF-kB signaling is frequently associated with inflammation and autoimmune diseases but the underlying mechanisms are not fully understood. Recent studies show that NF-kB plays a critical role in T-cell central tolerance. Two NF-kB signaling pathways have been identified: the canonical pathway and the alternative pathway. In the establishment of T-cell central tolerance, the alternative pathway appears to be the key signaling component in thymic stromal cells for their development and function, while the canonical pathway exerts its function more in autonomous T-cell selection. This review intends to summarize the current understanding of the role of NF-kB in establishing T-cell central tolerance and highlight unsolved intriguing questions for future work.

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“…Thymocyte interaction is required for the upregulation of MHCII expression during ontogeny; therefore, this change may reflect the reduced levels of thymopoiesis. Medullary TEC (mTEC) formation, differentiation, and expansion require signaling from thymocytes through receptor activator of nuclear factor kappa-B ligand and CD40L [13]. …”

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“…The NF-κB signaling pathway has an important role in regulating lymphocyte development and activation (13)(14)(15). NF-κB comprises a family of transcription factors, including RelA, RelB, c-Rel, NF-κB1 p50, and NF-κB2 p52, which form different dimeric complexes and transactivate target genes by binding to a κB enhancer (16,17).…”

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“…The former involves deletion or functional inactivation of autoimmune T cells during their development in the thymus, whereas the latter involves the action of regulatory T (Treg) cells to control the self-reactive T cells that have escaped from central tolerance induction (Hogquist et al, 2005; Josefowicz et al, 2012; Kyewski and Klein, 2006). The noncanonical NF-κB pathway plays a crucial role in regulating central tolerance (Zhu and Fu, 2010). Mice with deficiency in the noncanonical NF-κB members, RelB and NF-κB2, or kinases that mediate noncanonical NF-κB activation (NIK and IKKα) have compromised central tolerance and different levels of autoimmunity.…”

“…Mice with deficiency in the noncanonical NF-κB members, RelB and NF-κB2, or kinases that mediate noncanonical NF-κB activation (NIK and IKKα) have compromised central tolerance and different levels of autoimmunity. Noncanonical NF-κB regulates central tolerance by mediating the development of medullary epithelial cells (mTEC), which are required for thymic negative selection to delete autoreactive T cells (Zhu and Fu, 2010). …”