How do natural killer T cells help B cells?

Abstract

CD1d-restricted natural killer (NKT) cells are important contributors to antigen-specific antibody responses. There is, therefore, considerable interest in the design and implementation of strategies to appropriately activate NKT cells and boost vaccine-induced protective antibody responses. In order to achieve these goals, investigators are examining the mechanisms by which NKT cells enhance antibody responses. Although information is limited, it is now appreciated that both cognate and noncognate interactions between CD1d-expressing B cells and NKT cells drive enhanced antibody responses. NKT cells may provide B-cell help in the form of direct receptor-mediated interactions as well as by secretion of soluble effectors, including cytokines. In this article, we review the evidence in support of these mechanisms and discuss how they likely take place in the context of interactions of NKT cells with other cell types, such as dendritic cells and helper T cells. We also discuss the evidence that NKT cells affect discrete differentiation events in the multistep process by which a naive B cell experiences antigen and develops into a memory B cell or an antibody-secreting plasma cell. Since most information on NKT cells and humoral immunity has been derived from murine studies, we discuss what is known about human NKT cells and humoral immunity. We offer thoughts on whether the findings in murine systems will translate to humans.

Figure 1. Model for regulation of humoral immunity by natural killer T cells

(A) DCs that have captured T-cell-dependent Ags and CD1d-binding glycolipid Ags in the periphery drain to lymph nodes, process and present the Ags on class II and CD1d to the T-cell receptor of Th and NKT cells, respectively. These interactions are probably reinforced by B7:CD28 and CD40:CD154 interactions, leading to DC maturation and increasing Th priming and NKT interaction. The various cognate interactions between NKT cells and other cell types are shown in Figure 2. NKT cells may also facilitate enhanced Th priming. (B) The primed Th cells and activated NKT cells provide cognate help to B cells, resulting in clonal expansion, further cognate interaction in the secondary follicle and differentiation of some B cells into SLPCs. (C) Germinal center reactions occur, facilitated by FDCs, Th cells and possibly NKT cells, leading to successive rounds of positive and negative deletion, and the emergence of Bmem cells, which then differentiate into LLPC precursors, or self-renew to maintain the Bmem population. (D) LLPCs migrate to the bone marrow and compete for survival niches. Long-term survival is actively supported by stromal cell factors. Some NKT cells (including type 2) are present in BM and could potentially contribute to the survival of LLPCs. Questions indicate events that are not yet understood. Other parts of the model are supported by published work cited throughout the article. Ag: Antigen; Bmem: Memory B cell; DC: Dendritic cell; FDC: Follicular dendritic cell; GC: Galactosylceramide; LLPC: Long-lived plasma cell; NKT: Natural killer T cell; PC: Plasma cell; SLPC: Short-lived plasma cell; Th: T helper.

Figure 2. Possible cognate interactions between B cells and natural killer T cells during antibody responses

B cell to NKT cell CD1d:TCR interactions were shown to be important for α-GC-enhanced Ab responses against T-cell-dependent Ag [31,91] and for antibody responses against nitrophenol-α-GC [32]. Specific interactions between NKT cell CD154 and B cell CD40 or NKT cell CD28 and B cell B7 have not yet been demonstrated in the context of antibody responses but evidence cited herein suggests that these molecules are important. In this model, intracellular CD1d is loaded with glycolipid Ag captured via the BCR or LDLR and presented on the cell surface as CD1d/Ag complexes. CD1d/Ag and B7 engage the NKT TCR and CD28, respectively, leading to NKT activation and upregulation of CD154 expression. The increased CD154 expression leads to heightened engagement of CD40 on the B cell, providing important help for development and differentiation into memory B cells. It is likely that numerous as yet unidentified interactions take place between B cells and NKT cells. Not shown are interactions with Th cells, which will utilize similar cognate interactions, while presenting T-cell-dependent Ag-derived peptide Ag on class II. Ag: Antigen; GC: Galactosylceramide; LDLR: Low-density lipoprotein receptor; NKT: Natural killer T cell; TCR: T-cell antigen receptor.