Requirements for the natural killer cell-mediated induction of IgG1 and IgG2a expression in B lymphocytes

Abstract

Upon interaction with resting B lymphocytes, IL-2-propagated NK cells can initiate the process of Ig constant region switch recombination (CSR) by inducing germ line transcripts for gamma2a (Igamma2a) as well as increased levels of mRNA for activation-induced cytidine deaminase enzyme. Whereas both these processes are necessary for CSR, they are not sufficient because the cells do not proceed to the expression of mature mRNA for gamma2a (VDJCgamma2a). In addition, NK cells can also upregulate mRNA for the T-box transcription factor (T-bet) in B cells without being able to induce further differentiation. Using transgenic B cells with B cell receptor specificity for nitrophenol (NP), we have now shown that NP-Ficoll-stimulated B cells can be induced by NK cells to express IgG2a as well as IgG1 presumably due to the completion of the process of switch recombination. The inductive ability of NK cells does not require IFN-gamma but does require signals transmitted via CD48 by direct cell contact. In addition, NP-Ficoll on its own can induce proliferation of antigen-specific B cells as well as germ line transcripts of gamma1; however, expression of VDJCgamma1 mRNA also requires NK cell interaction with B lymphocytes. Therefore, in the presence of antigen, NK cells can provide a necessary signal that substitutes for cytokines in the induction of IgG2a as well as IgG1 expression. This in vitro analysis provides a mechanistic basis for understanding the documented NK cell effects on T-independent B cell responses in vivo.

A Novel and Divergent Role of Granzyme A and B in Resistance to Helminth Infection

“…The Th2 cytokine bias in gzmA3B ko mice might have promoted this, as IL-4 promotes IgG1, but blocks class switching to IgG2b in response to LPS (24). NK cells, which were enhanced early in wt mice, could also have promoted IgG2c production in wt mice (25).…”

Enhancement of Antigen-Specific Immunoglobulin G Responses by Anti-CD48

“…Crosslinking of CD48 on NK cells leads to aggregation of CD244 on the same cell, resulting in phosphorylation of tyrosine residues and subsequent activation of -cytokine production [6]. In vitro experiments utilizing interleukin (IL)-2-propagated NK cells have indicated that stimulation of B cells by NK cells requires the presence of CD48 on B cells and leads to interferon (IFN)-γ-independent activation of downstream exons of the immunoglobulin (Ig) locus as revealed by germline transcriptions [7,8]. However, this activation does not result in productive DNA recombination, leading to the expression of functional transcripts unless the cells are also stimulated via the B-cell receptor [8].…”

“…In vitro experiments utilizing interleukin (IL)-2-propagated NK cells have indicated that stimulation of B cells by NK cells requires the presence of CD48 on B cells and leads to interferon (IFN)-γ-independent activation of downstream exons of the immunoglobulin (Ig) locus as revealed by germline transcriptions [7,8]. However, this activation does not result in productive DNA recombination, leading to the expression of functional transcripts unless the cells are also stimulated via the B-cell receptor [8]. On mast cells, CD48 itself may have receptor activity as well [9].…”

Mechanism of Induction of NK Activation by 2B4 (CD244) via Its Cognate Ligand

“…Murine 2B4 (CD244), the first member of the SLAM family identified (3,4), is expressed on all NK cells and on some T cells (4,5). Whereas 2B4 functions mainly as an activating receptor on human NK cells, on murine NK cells 2B4 has been shown to exert both activating and inhibitory effects on the cytotoxic activity of NK cells (4,(6)(7)(8)(9)(10). Unlike most of the other SLAM family members that have self-ligands, 2B4 has a unique ligand, CD48 (6).…”

“…Using this approach, we have shown previously that some subsets of B cells are effective inducers of NK cell activation via the CD48-2B4 interaction (7). In addition, 2B4 can also function as a ligand to activate B cells via CD48, although CD2 is a more effective stimulator in this case (8). In an effort to understand how CD48 activates NK cells, we have extensively analyzed the effect of ligation of CD48 by anti-CD48 on NK cells.…”