Also observed by Galli and co-workers (28), we found that IgE was not induced by any of the 3 iNKT cell subsets

Also observed by Galli and co-workers (28), we found that IgE was not induced by any of the 3 iNKT cell subsets. subsets could induce CD40 and CD86 manifestation by B cells, iNKT cell-matured B cells were unable to drive proliferation of autologous and alloreactive standard T cells, as seen with B cells cultured in the absence of iNKT cells. Consequently, human CD4+, CD8+and DN iNKT cells can differentially promote and regulate the induction of antibody and T cell reactions by B cells. == Intro == T cell-dependent B cell reactions require engagement of antigen from the BCR resulting in antigen internalization, processing and cell-surface demonstration on MHC molecules (13). Upon acknowledgement of cognate peptide-MHC class II complexes, the T cell upregulates CD40L which engages CD40 within the B cell, inducing proliferation and differentiation. The T cell also secretes cytokines that are required for immunoglobulin isotype switching. Cognate T cell-B cell relationships can result either SB-277011 in extrafollicular proliferation of B cells into short-lived plasmablasts that do not undergo affinity maturation and mediate transient innate-like reactions (2), or germinal centre proliferation of B cells which undergo somatic hypermutation and affinity maturation resulting in the generation of long-lived plasma cells or memory space B cells (3). Invariant natural killer T (iNKT)5cells can provide help for B cell maturation and antibody production. iNKT cells are cytotoxic T cells that communicate a TCR composed of an invariant -chain (V14J18 in mice and V24J18 in humans) that pairs with a limited quantity of -chains and recognizes glycolipid antigens offered from the MHC class I-like molecule CD1d (4,5). iNKT cells are thought to play central functions in innate and adaptive immunity through their ability to activate or induce differentiation of NK cells (6), dendritic cells (DC)5(7,8) and T cells (9) and to launch multiple helper T (Th) cell-polarising cytokines (1013). iNKT cells can also regulate, enhance and sustain humoral immune reactions. In murine models, CD1d and iNKT cells are required for the generation of protecting antibody reactions against pathogens, includingPlasmodium falciparum(14),Streptococcus pneumoniae(15) andBorreliaspecies (16). CD1d and iNKT cells will also be required for the production of allergen-specific IgE in an experimental asthma mouse model (17). The adjuvant effect of iNKT cells on humoral immune responses is definitely antigen-specific. Co-administration of the iNKT cell agonist ligand -galactosylceramide (-GC)5with immunizing antigen to mice results in enhanced production of antibodies specific for the antigen (1820). This help provided by iNKT cells results in the induction of long-lived antibody-secreting plasma cells, affinity maturation and the generation of memory space B cells (2022). iNKT cells can also provide help for B cells specific for lipid-containing antigens internalized through the BCR (23,24). Such B cell help results in the formation of extrafollicular plasmablasts and germinal centres, affinity maturation and strong IgG antibody reactions but not long-lived memory space cells (25). Although iNKT cells communicate semi-invariant TCRs, they can be divided into unique populations based on CD4 and CD8 expression. Humans have varying ratios of CD4+CD8(CD4+), CD4CD8(double-negative or DN)5and CD4CD8+(CD8+) iNKT cells (11,13,26). CD4+iNKT cells launch probably the most Th2 cytokines and CD8+and DN iNKT cells mainly show Th1 phenotypes and cytotoxic activity (11,13,27). To day, 2 studies (28,29) have examined the relative contributions of human being iNKT cells subsets to B cell help and found that both CD4+and CD4iNKT cells similarly induced B cell proliferation, but CD4+iNKT cells induced higher levels of SB-277011 antibody production. In addition to their functions in antibody production, B cells are potent APCs that can prime CD4+T cells without the participation Rabbit Polyclonal to C-RAF of DCs or macrophages (30). Much like DC, B cells can create both Th1- and Th2-type cytokines and may become polarized towards one or the additional subset subsequent to interaction with CD4+Th1 or Th2 cells (31). The unique capabilities of iNKT cells to selectively secrete Th1, Th2, Th17 or regulatory T cell SB-277011 cytokines (1013) and to induce DC maturation (7,8,32) led us to hypothesise that iNKT cells may exert stimulatory and/or regulatory control over antigen demonstration and T cell activation by B cells. Here we have examined the outcomes of culturing human being peripheral B cells with expanded autologous iNKT cells or sorted CD4+, CD8+and DN iNKT cell subsetsin vitro, in the absence or presence of -GC. We display the iNKT cell subsets differentially induce phenotypic differentiation, antibody secretion and T cell activation by B cells. We also display that CD4+iNKT cells promote the.