Nuclear factor-κB1 controls the functional maturation of dendritic cells and prevents the activation of autoreactive T cells

Dilan Dissanayake ,. et al. 2012. Nature Med 7, 1663-7

Speaker: Zhou Yu (周 妤)                                             Time: 14:00~15:00, March 21, 2012

Commentator: Yee-Shin Lin, Ph.D. (林以行老師)       Place: Room 601

Abstract:

Dendritic cells (DCs) are antigen-presenting cells which play a critical role in the regulation of the adaptive immune response. Mature DCs are defined by key morphological features and the presence of various molecules on the cell surface, such as Toll-like receptors (TLRs) which canrecognize microbial products, and the upregulation of major histocompatibility complex (MHC) and co-stimulatory molecules, as well as the secretion of cytokines that shape the nature and amplitude of the adaptive response directed against the microbes. NF-kB is a homo- or heterodimericcomplex formed by the Rel-like domain-containing proteins p50, p52, p65 (RelA), c-Rel, and RelB. The p50 and p52 are proteolytically-processed products from the p105 (NF-κB1) and p100 (NF-κB2), respectively, under stimulation. NF-kB plays a key role for mediating DC maturation and the acquisition of the functions required for full activation of T cells, but how exactly role of NFkB in DCs maturation still unclear. In this study, authors used the transgenic mice (RIP-gp) expressing the lymphocytic choriomeningitis virus (LCMV) glycopro­tein (gp) on pancreatic islet beta cells under the control of the rat insulin promoter (RIP) as a autoimmune diabetes model. By transferring gp-derived epitopes-pulsed bone marrow–derived DCs into mice with or without CpG oligodeoxynucleotides stimulation, they found the induction of CD8+ T cell-mediated diabetes is DC maturation dependent. Then, they discovered NF-κB1–deficient DCs do not require TLR stimulation to induce diabetes and also found this situation did not upregulate makers of DC maturation but lead to spontaneous TNF-α production. In order to test the specific requirement of TNF-α in the induction of diabetes, they generated Nfkb1−/−;Tnf−/− mice and found the expression level of granzyme B, which is a key mediator of beta cell destruction in diabete, was markedly reduced. They concluded that induction of diabetes in RIP-gp mice by transferred DCs is dependent upon TNF-α production. In summary, a new knowledge of NF-κB1 which plays a negative role in regulating TNF-α production of resting DCs and preventing the sub­sequent induction of CD8+ effector activity.

References:

1.      Sha, W.C., et al. 1995. Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immune responses. Cell 80, 321–330.

2.      Ohashi, P.S.,et al. 1991. Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65, 305–317.