Human Invariant NKT Cell Subsets Differentially Promote Differentiation, Antibody Production, and T Cell Stimulation by B Cells In Vitro

Abstract

Invariant natural killer T (iNKT) cells can provide help for B cell activation and antibody production. Since B cells are also capable of cytokine production, antigen presentation and T cell activation, we hypothesized that iNKT cells will also influence these activities. Furthermore, subsets of iNKT cells based on CD4 and CD8 expression that have distinct functional activities may differentially affect B cell functions. We investigated the effects of co-culturing expanded human CD4+, CD8α+ and CD4−CD8α− double negative (DN) iNKT cells with autologous peripheral B cells in vitro. All iNKT cell subsets induced IgM, IgA and IgG release by B cells without needing the iNKT cell agonist ligand α-galactosylceramide (α-GC). Additionally, CD4+ iNKT cells induced expansions of cells with phenotypes of regulatory B cells. When co-cultured with α-GC-pulsed B cells, CD4+ and DN iNKT cells secreted Th1 and Th2 cytokines but at 10–1,000-fold lower levels than when cultured with dendritic cells. CD4+ iNKT cells reciprocally induced IL-4 and IL-10 production by B cells. DN iNKT cells expressed the cytotoxic degranulation marker CD107a upon exposure to B cells. Remarkably, while iNKT cell subsets could induce CD40 and CD86 expression by B cells, iNKT cell-matured B cells were unable to drive proliferation of autologous and alloreactive conventional T cells, as seen with B cells cultured in the absence of iNKT cells. Therefore, human CD4+, CD8α+ and DN iNKT cells can differentially promote and regulate the induction of antibody and T cell responses by B cells.

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

“…This finding was later confirmed using fresh human iNKT cells [180]. In our own work, we investigated the effects of co-culturing expanded human CD4 + , CD8a + and CD4 À CD8a À iNKT cells with autologous peripheral B cells in vitro and found that all iNKT cell subsets induced IgM, IgA and IgG release by B cells by a mechanism that required CD1d but not added glycolipid, such as a-GC [181]. All iNKT cell subsets induced the expression of CD40, CD86 and HLA-DR by B cells, but iNKT cell-matured B cells were less able to drive proliferation of autologous and alloreactive conventional T cells than B cells cultured in the absence of iNKT cells.…”

“…Additionally, CD4 + iNKT cells induced expansions of cells with phenotypes of regulatory B cells. Therefore, human iNKT cell subsets may differentially promote and regulate antibody production and T cell activation by B cells [181].…”

ABO, alemtuzumab and allogeneic transplantation

“…13,14 iNKT cells are a small but critical T-cell population involved in the B-cell response to glycolipid antigens via CD1d, a major histocompatibility complex-like molecule. 14 iNKT cells promote B-cell proliferation, B memory responsiveness, plasma cell generation and antibody production.…”

“…14 iNKT cells promote B-cell proliferation, B memory responsiveness, plasma cell generation and antibody production. 14,15 Their relative absence in common variable immunodeficiency may contribute to both B-cell defects and hypogammaglobulinemia. Recent studies suggest that iNKT can stimulate B-cell proliferation and antibody production through cell-cell contact, probably due to the expression of stimulatory glycolipid self-antigens on B cells.…”

“…Recent studies suggest that iNKT can stimulate B-cell proliferation and antibody production through cell-cell contact, probably due to the expression of stimulatory glycolipid self-antigens on B cells. 14,15 Recently, iNKT cells were identified as necessary for the development of allo-anti-A formation in a murine mouse model. 16 Tazawa et al 16 were able to induce high-titer anti-A in wild-type mice after repeated injections with group A human red cells, whereas little or no anti-A was observed in nude mice, which are deficient in iNKT cells.…”