Invariant NKT cells provide innate and adaptive help for B cells

Abstract

B cells rely on CD4(+) T cells helper signals to optimize their responses to T-dependent antigens. Recently another subset of T cells has been identified which provides help for B cells, invariant natural killer T (iNKT) cells. iNKT cells are unique because they provide both innate and adaptive forms of help to B cells, with divergent outcomes. iNKT cells are widely distributed throughout the spleen at rest, consolidate in the marginal zone of the spleen early after activation, and are later found in germinal centers. Understanding the activation requirements for iNKT cells has led to the development of glycolipid containing nanoparticles which efficiently activate iNKT cells, enhance their cooperation with B cells, and which hold promise for vaccine development.

Figure 1. iNKT cells provide innate, cognate help as well as adaptive, noncognate help for antigen-specific B cells

Innate iNKT_FH cells recognize glycolipid-loaded CD1d on B cells and directly provide helper signals including CD40L, CD28, IL-21, and IFNγ which initiate plasmablast (PB) expansion, early germinal center B cell (GC B) development, modest affinity maturation, and primary class-switched antibody production. This direct form of help constitutes innate help and is specific for T-dependent type II antigens. Alternatively, iNKT_FH cells can recruit non-cognate or adaptive help by engaging DCs presenting glycolipids in the context of CD1d and licensing the DC to enhance MHC class II antigen presenting capabilities and upregulate costimulatory molecules such as CD40 to engage and activate CD4+ T cells. The peptide-specific CD4+ T cells then go on to provide help for protein-specific B cells which initiates development of plasmablasts, mature germinal centers, robust affinity maturation, primary class-switched antibody production by plasma cells (PC) and ultimately memory cells (B_mem). CD4+ T cells also benefit from iNKT cell- secreted IL-2, IL-4, BAFF, and APRIL. This adaptive form of iNKT cell help is capable of generating humoral memory and is elicited in response to T-dependent type I and T-independent antigens paired with a glycolipid adjuvant.

Figure 2. iNKT cell localization varies during the course of an immune response

Endogenous, resting iNKT cells are localized widely throughout the parenchyma of the spleen. At points of peak effector cytokine secretion induced by cognate glycolipid (4 hours) or systemic infection with Streptococcus pneumoniae (8 hours) the iNKT cells consolidate in the marginal zone (MZ). Alternatively, iNKT cells become activated to secrete effector cytokine in place without relocalizing 2 hours after stimulation by systemic IL-12 and IL-18. Finally, 3 days after activation with cognate glycolipid iNKT cells can be found in germinal centers (GCs). (Periarteriolar lymphoid sheath, PALS)