NF-κB in immunobiology

Abstract

NF-κB was first discovered and characterized 25 years ago as a key regulator of inducible gene expression in the immune system. Thus, it is not surprising that the clearest biological role of NF-κB is in the development and function of the immune system. Both innate and adaptive immune responses as well as the development and maintenance of the cells and tissues that comprise the immune system are, at multiple steps, under the control of the NF-κB family of transcription factors. Although this is a well-studied area of NF-κB research, new and significant findings continue to accumulate. This review will focus on these areas of recent progress while also providing a broad overview of the roles of NF-κB in mammalian immunobiology.

Figure 1

The mammalian NF-κB, IκB and IKK protein families. Relevant domains typifying each protein family are indicated and alternative nomenclatures are provided in parenthesis. The precursor proteins p100 and p105 function as both IκB and, when processed by the proteasome, NF-κB family members. Highly simplified schematics of canonical and non-canonical NF-κB pathways are shown. In the canonical pathway NEMO-containing IKK complexes are activated and induce phosphorylation and degradation of IκBα leading to the release of NF-κB dimers including p65:p50 dimers. In the non-canonical pathway, NEMO-independent activation of IKKα is mediated by the upstream kinase NIK. IKKα, with NIK, induces phosphorylation and processing of p100 to p52 resulting in the activation of predominantly p52:RelB complexes. Although they are illustrated separately here, as discussed in the text, signaling through these two pathways often is initiated by the same receptor – e.g., LTβR or CD40. (ANK, ankyrin-repeat domain; DD, death domain; RHD, REL homology domain; TAD, transactivation domain; LZ, leucine-zipper domain; GRR, glycine-rich region; HLH, helix-loop-helix domain; Z, zinc-finger domain; CC, coiled-coil domain; NBD, NEMO-binding domain; MOD/UBD, minimal oligomerization domain/ubiquitin-binding domain; PEST, proline, glutamic acid, serine, and threonine rich.)

Figure 2

NF-κB in lymphoid organogenesis. NF-κB regulates key components of a positive feedback loop between hematopoietic and stromal cells. LTα₁β₂-expressing hematopoietic cells induce production of VCAM-1 through the canonical NF-κB pathway and chemokines through the non-canonical pathway in LTβR-expressing stromal cells. Stromal expression of chemokines induces the upregulation of integrins (α₄β₁) on hematopoietic cells resulting in increased recruitment of LTα₁β₂-expressing cells, and increased signaling through stromal LTβR. RANKL signaling through RANK on the hematopoietic cell leads to activation of NF-κB, and further upregulation of LTα₁β₂.

Figure 3

NF-κB in hematopoiesis. Red arrows indicate stages in which NF-κB activation is thought to contribute negatively and green arrows indicate a positive function in the development of the indicated lineages. Curved arrows indicate examples in which NF-κB contributes to the survival of cell population, either in the resting state or during immune responses. Gray arrows indicate developmental events for which NF-κB plays no role or for which the role of NF-κB has not been clearly demonstrated. (HSC, hematopoietic stem cell; CMP, common myeloid progenitor; MLP, myeloid/lymphoid progenitor; MEP, megakaryocyte erythrocyte progenitor; GMP, granulocyte monocyte progenitor; MDP, macrophage dendritic cell progenitor; CDP, common dendritic cell progenitor; CLP, common lymphoid progenitor; ETP, early thymic precursor; and B/NP, B-cell natural killer cell progenitor).

Figure 4

NF-κB in lymphopoiesis. NF-κB plays a pro-survival role in common lymphoid precursor (CLP) cells which give rise to B- and T-cell lineages. B-cell development occurs in the bone marrow, where NF-κB protects pre-B cells from pro-apoptotic stimuli including TNFα. Signaling to NF-κB through the pre-B cell receptor mediates survival of Pre-B cells, which then undergo light chain recombination to produce a functional B cell receptor. NF-κB provides a necessary pro-survival signal during Igλ but not Igκ rearrangement. Expression of BCR leads to NF-κB-dependent differentiation into immature B cells. High levels of BCR signaling, i.e., through recognition of self-antigen, results in negative selection through the loss of NF-κB activity. Transitional B cells exit the bone marrow and migrate to the spleen, where they mature and differentiate, a process that also requires NF-κB. T-cell development occurs following migration of precursor cells into the thymus. Stimulation of NF-κB through pre-TCRα provides a pro-survival signal allowing recombination of the TCR α chain and maturation to the double-positive (DP) stage. Optimal signaling through the TCRα/β complex induces NF-κB-dependent survival pathways, while a failure to signal or high level signaling results in death by neglect or negative selection, respectively. Intermediate high NF-κB activation facilitates intrathymic regulatory T cell (Treg) development. NF-κB activity is required for the maintenance of long-lived B and T cells. (CLP, common lymphoid progenitor; ETP, early thymic progenitor; DN, double negative – CD4⁻CD8⁻; DP, double positive – CD4⁺CD8⁺; SP, single positive – either CD4⁺CD8⁻ or CD4⁻CD8⁺)

Figure 5

Pattern recognition receptors and their cognate ligands. TLRs 3, 7, 8, 9 and 11 have been reported to exhibit endosomal or intracellular localization while NOD1, NOD2, RIG-I, MDA-5, NALP1, NALP3, NLRC4, and the intracellular DNA sensor (ISD) function in the cytoplasm. Only a partial list of ligands or classes of ligands for each receptor is given.

Figure 6

NF-κB in T cell activation. NF-κB participates in the maintenance, activation, differentiation and proliferation of naive T cells. Tonic TCR stimulation promotes T cell maintenance, of both memory and naive cells, through NF-κB activation. Activation occurs when the naive T cell recognizes its cognate antigen presented by an activated APC expressing both peptide:MHC and B7 family co-stimulatory molecules. NF-κB-dependent proliferation and differentiation ensue and are influenced by the local cytokine milieu. NF-κB supports proliferation, differentiation and survival as indicated (green arrows).

Figure 7

T_H cell differentiation. NF-κB participates in differentiation of several T_H cell types following activation of naive CD4⁺ T_H cells. Differentiation pathways in which NF-κB is implicated are indicated with a green arrow. Key transcription factors in each differentiation pathway are indicated above each arrow, while cytokine responsible for skewing T_H cells toward a given pathway are indicated below each arrow. Additional cytokines and transcription factors implicated in several of the pathways are not depicted.

Figure 8

NF-κB in B cell activation. NF-κB participates in the maintenance, activation, differentiation and proliferation of naive B cells. Tonic BCR and cytokine, BAFF, stimulation promotes naive B cell maintenance through NF-κB activation. Activation occurs when the naïve B cell recognizes its cognate antigen and receives co-stimulatory signaling (CD40L) from an activated T_H cell within the germinal center. NF-κB-dependent proliferation and differentiation ensue and are coupled to BCR affinity maturation. NF-κB signaling in B cells expressing selected BCRs results in class switch recombination and differentiation into either memory B cells or plasma cells. NF-κB supports proliferation, differentiation and survival as indicated (green arrows).