Activation and Regulation of B Cell Responses by Invariant Natural Killer T Cells

Abstract

CD1d-restricted invariant natural killer T (iNKT) cells play central roles in the activation and regulation of innate and adaptive immunity. Cytokine-mediated and CD1d-dependent interactions between iNKT cells and myeloid and lymphoid cells enable iNKT cells to contribute to the activation of multiple cell types, with important impacts on host immunity to infection and tumors and on the prevention of autoimmunity. Here, we review the mechanisms by which iNKT cells contribute to B cell maturation, antibody and cytokine production, and antigen presentation. Cognate interactions with B cells contribute to the rapid production of antibodies directed against conserved non-protein antigens resulting in rapid but short-lived innate humoral immunity. iNKT cells can also provide non-cognate help for the generation of antibodies directed against protein antigens, by promoting the activation of follicular helper T cells, resulting in long-lasting adaptive humoral immunity and B cell memory. iNKT cells can also regulate humoral immunity by promoting the development of autoreactive B cells into regulatory B cells. Depletions and functional impairments of iNKT cells are found in patients with infectious, autoimmune and malignant diseases associated with altered B cell function and in murine models of these conditions. The adjuvant and regulatory activities that iNKT cells have for B cells makes them attractive therapeutic targets for these diseases.

Keywords: B cells; CD1d; antibodies; disease; glycolipids; invariant natural killer T cells.

Figure 1

Invariant natural killer T (iNKT) cells activate and regulate multiple cells of the innate and adaptive immune systems. Cytokines released by iNKT cells contribute to the activation and polarization of CD4⁺ and CD8⁺ T cells and natural killer (NK) cells. Cytokines and CD1d-dependent interactions between iNKT cells and dendritic cells (DCs), macrophages, neutrophils, and myeloid-derived suppressor cells (MDSC) lead to the activation and regulation of the effector activities of these cells.

Figure 2

Invariant natural killer T (iNKT) cells provide non-cognate and cognate help for antigen-specific B cells. (A) Coadministration of protein antigen and an iNKT cell ligand, such as α-galactosylceramide (lipid antigen) results in internalization by a dendritic cell (DC) and simultaneous presentation of peptide fragments of the protein antigen on major histocompatibility complex (MHC) class II to a naïve CD4⁺ T cell and of the lipid antigen on CD1d to iNKT cells. IFN-γ production by the iNKT cell reciprocally promotes MHC class II antigen presentation and expression of CD40 by the DC, whereas IL-2, IL-4, B cell activation factor (BAFF), and a proliferation-inducing ligand (APRIL) production promotes maturation of the peptide-specific CD4⁺ T cell into a follicular helper T (T_FH) cell. The T_FH cell then provides antigen-specific help for the proliferation of B cells in germinal centers, affinity maturation, antibody class switching, and the generation of long-lived antibody-secreting plasma cells and memory B cells. (B) iNKT cells recognizing lipid antigens presented by DC differentiate into follicular helper invariant natural killer T (iNKT_FH) cells capable of activating B cells specific for lipid antigens or proteins or haptens conjugated to the lipid antigens. B cell activation is mediated by CD40 and CD80/86 ligation by the iNKT_FH cells and the production of IL-21 and IFN-γ. Cognate B cell help from iNKT cells results in plasmablast expansion, germinal center formation, modest affinity maturation, and primary class switched antibody production.