Essential Role of IκB Kinase α in Thymic Organogenesis Required for the Establishment of Self-Tolerance

Abstract

IκB kinase (IKK) α exhibits diverse biological activities through protein kinase-dependent and -independent functions, the former mediated predominantly through a noncanonical NF-κB activation pathway. The in vivo function of IKKα, however, still remains elusive. Because a natural strain of mice with mutant NF-κB-inducing kinase (NIK) manifests autoimmunity as a result of disorganized thymic structure with abnormal expression of Rel proteins in the thymic stroma, we speculated that the NIK-IKKα axis might constitute an essential step in the thymic organogenesis that is required for the establishment of self-tolerance. An autoimmune disease phenotype was induced in athymic nude mice by grafting embryonic thymus from IKKα-deficient mice. The thymic microenvironment that caused autoimmunity in an IKKα-dependent manner was associated with defective processing of NF-κB2, resulting in the impaired development of thymic epithelial cells. Thus, our results demonstrate a novel function for IKKα in thymic organogenesis for the establishment of central tolerance that depends on its protein kinase activity in cooperation with NIK.

NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

“…[50][51][52][53][54][55][56][57] As opposed to mTECs, cTEC number is not affected in mice with defect in the alternative NF-κB pathway. 58 However, in our study, we highlight a new role for NIK downstream of LTβR in induction of TNFR1-driven cTEC death and thymus involution.…”

NF-κB and the immune response

“…However, the role of the non-canonical pathway, as assessed by examining mice deficient for IKKa, p52, NIK or RelB, is especially important both during organogenesis and maintenance of splenic architecture. Recent data suggest that the non-canonical pathway is also important in thymic development and organization (Burkly et al, 1995;Weih et al, 1995;Kajiura et al, 2004;Kinoshita et al, 2006). However, it is important to note that canonical NF-kB pathway function in these events may be underappreciated owing to embryonic lethality and complicated by the defects introduced by crossing them onto the tnfr À/À background.…”

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).…”