Roles of the NF-kappaB pathway in lymphocyte development and function

Abstract

This article focuses on the functions of NF-kappaB that vitally impact lymphocytes and thus adaptive immunity. NF-kappaB has long been known to be essential for many of the responses of mature lymphocytes to invading pathogens. In addition, NF-kappaB has important functions in shaping the immune system so it is able to generate adaptive responses to pathogens. In both contexts, NF-kappaB executes critical cell-autonomous functions within lymphocytes as well as within supportive cells, such as antigen-presenting cells or epithelial cells. It is these aspects of NF-kappaB's physiologic impact that we address in this article.

Figure 1.

NF-κB in thymic T-cell development. Shown is a schematic and simplified representation of thymic T-cell development, highlighting stages at which NF-κB contributes in a cell-autonomous fashion. Also highlighted is the requirement of NF-κB for generation of medullary thymic epithelial cells (mTECs). γδ T cells and Tβ-expressing thymocytes can be distinguished at the (CD4, CD8) double negative (DN) stage III b. The pre-TCR (pTα/Tβ) drives development of thymocytes into DN IV cells, which in turn give rise to double positive (DP) cells (αβTCR). Positive selection of DP thymocytes to become CD4 or CD8 single-positive (SP) thymocytes is driven by weak recognition of self-AGs presented on cortical thymic epithelial cells in the context of MHC class II or class I, respectively. T-regulatory cells (Tregs, FoxP3+) and NKT cells may develop from DP thymocytes by recognition of self-AGs with intermediate strength (lipids presented on CD1d in the case of NKT cells). Failure to recognize self-AGs leads to elimination of thymocytes (death by neglect); strong recognition of self-AGs also leads to elimination (negative selection). Negative selection begins in the cortex but may occur predominantly in the medulla, where self-AGs are presented on dendritic cells (DCs) and on mTECs. mTECs produce tissue-specific (self)-AGs (TSAs) and can cross-prime DCs with these antigens. See text for further details.

Figure 2.

NF-κB in B cell development. A schematic and simplified representation of bone marrow and splenic B-cell development, highlighting stages at which NF-κB contributes in a cell-autonomous fashion to formation of marginal zone (MZ B) and follicular mature (FM) B cells; the latter are also known as B2 B cells and enter the peripheral circulation. Also highlighted is the requirement for NF-κB in B1 B-cell development, a peripherally self-renewing population with precursors in fetal liver and possibly bone marrow. Also highlighted is the importance of NF-κB in stromal cells/follicular dendritic cells (FDCs) in forming a proper splenic architecture (B-cell follicles, marginal zone) and in forming Peyer’s patches and lymph nodes. B-cell development commences in the bone marrow, where the pre-BCR on large pre-B cells (a.k.a. late pro-B) drives development into small (late) pre-B cells, which in turn give rise to immature B cells (first to express a full BCR [IgM]). Self-antigen (AG)-reactive immature B cells edit their receptors by further light chain gene rearrangements or they are eliminated (negative selection). Surviving immature and “more mature” immature B cells (T2-like) then migrate to the spleen (white pulp), where they progress through the transitional 1 (T1) and T2 stages to become FM (located in B cell follicles) and MZB cells (located in marginal zones). Early transitional-staged cells continue to be subject to negative selection. Generation of FMs and MZBs from early transitional stages is driven by signals from the BCR, BAFFR, and other receptors (“+”) to assure survival, but also to regulate cell differentiation (“+”) in part via NF-κB. (Additional minor pathways and populations have been postulated, but are not shown here.) See text for further details.

Figure 3.

NF-κB in B-cell activation. The activation of follicular B cells by CD4 T-cell-dependent CD40 and BCR signals promotes a rapid antigen-driven expansion of B cells in the germinal centers (GC) of secondary lymphoid organs that is accompanied by isotype switching and affinity maturation. These antigen and cytokine driven events lead to the development of long-lived plasma cells and memory B cells. Shown are the requirements for NF-κB during the various phases of B-cell differentiation and proliferation.

Figure 4.

Roles of NF-κB in B-cell division. Following stimulation through the BCR, CD40, or TLR4/TLR9, mature quiescent B cells in G0 enter G1 and undergo an NF-κB dependent phase of growth. B-cell growth continues until late G1, at which point NF-κB is required for entry into S-phase. Subsequent steps in the B-cell cycle appear to be NF-κB independent. NF-κB also regulates survival signals associated with B-cell activation and division.

Figure 5.

NF-κB in conventional T-cell activation. TCR-dependent activation of naïve CD4 and CD8 T cells by antigen presenting cells (APC) leads to T-cell activation, division, and effector T-cell differentiation. The various CD4 T helper cell subsets and CD8 cytotoxic T lymphocytes that develop in response to different cytokine and costimulatory signals delivered by APC and T cells undergo rapid antigen-driven expansion during the course of an infection. Following pathogen elimination, most effector T cells undergo activation-induced cell death, with the few surviving antigen-specific T cells differentiating into long-lived memory cells. Highlighted are roles for NF-κB in APC function, T-cell activation, CD4 Th differentiation, and T-cell survival and proliferation.