Human B Cell Activation by Autologous NK Cells Is Regulated by CD40-CD40 Ligand Interaction: Role of Memory B Cells and CD5+ B Cells

Blanca, Isaac; Bere, Earl W.; Young, Howard A.; Ortaldo, John R.

doi:10.4049/jimmunol.167.11.6132

Cited by 89 publications

(70 citation statements)

References 46 publications

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“…Indeed, several lines of evidence indicate that NK cells may be capable of providing efficient help to B cells (45,46) and may also express CD40L (47), another factor that is essential in providing costimulatory signals to Ag-primed B cells for survival, Ig class switch, and generation of memory B cells (48,49). In our nude mouse model we could demonstrate the expression of both IFN-␥ and CD40L by NK cells present in draining lymph nodes of N592/IL-12/IL-15-primed animals, which were capable of rejecting N592pc upon rechallenge.…”

Section: Discussionmentioning

confidence: 99%

Tumor Cells Engineered with IL-12 and IL-15 Genes Induce Protective Antibody Responses in Nude Mice

Orengo

Carlo

Comes

et al. 2003

The Journal of Immunology

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IL-12 and IL-15 stimulate T, B, and NK cell functions through independent mechanisms, and cooperative effects of these cytokines have been reported. The human MHC class I-negative small cell lung cancer cell line, N592, genetically engineered to secrete IL-15, N592/IL-15, showed a reduced tumor growth rate, while N592 cells engineered with IL-12, N592/IL-12, grew similarly to the wild-type N592, N592 parental cells (N592pc), in nude mice. However, N592 cells coexpressing both cytokines, N592/IL-12/IL-15 cells, were completely rejected by 100% of nude mice. Here we show that 60% of nude mice rejecting N592/IL-12/IL-15 cells were resistant to N592pc rechallenge. SCID mice rejected N592/IL-12/IL-15 cells, but did not develop resistance to N592pc rechallenge, suggesting a role of Ab responses. Among nude mice rejecting N592/IL-12/IL-15 cells, those developing resistance to N592pc rechallenge had significantly higher titers of anti-N592 IgG2b Abs than nonresistant nude mice. Induction of an Ig class switch in nude mice was related to the expression of IFN-γ and CD40 ligand in the draining lymph nodes. An IgG2b, anti-N592 mAb, derived from N592/IL-12/IL-15-immunized nude mice splenocytes induced significant protection against N592pc, while an IgM mAb was ineffective. The protective IgG2b mAb, but not the IgM mAb, triggered Ab-dependent cell-mediated cytotoxicity by nude mouse splenocytes against N592pc. These data indicate that IL-12 and IL-15 synergistically trigger innate, immunity-mediated, anti-tumor effects, resulting in cytotoxic IgG Ab responses in T cell-deficient mice. Protective Ab responses may relate to both direct actions of IL-12 and IL-15 on B cells and to the activation of an innate immunity-B cell cross-talk.

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Section: Discussionmentioning

confidence: 99%

Tumor Cells Engineered with IL-12 and IL-15 Genes Induce Protective Antibody Responses in Nude Mice

Orengo

Carlo

Comes

et al. 2003

The Journal of Immunology

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“…2B in which the relative levels of induced I␥2a transcripts is shown as a percentage of the levels induced in the absence of inhibitors. Thus, neither anti-CD28 nor anti-CD40L, both hamster Abs directed against ligands previously reported to be on NK cells (16,29,36), altered the level of induction of I␥2a transcription nor did a hamster Ab against TCR␣␤ chains, added as a specificity control, because they are not expressed on the purified, IL-2-propagated NK cells. Therefore, it is unlikely that cross-linking of NK cells to B cells by virtue of the binding of the Ig Fc portion to the B cell FcRII affected the induction.…”

Section: Inhibition Of Induction Of I␥2a Transcription By Abs Againstmentioning

confidence: 99%

Receptors and Counterreceptors Involved in NK-B Cell Interactions

Gao

Dang

Dunnick

et al. 2005

The Journal of Immunology

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In addition to the well-documented effect of NK cells on B cell differentiation via their ability to secrete IFN-γ, NK cells can also induce, via direct cell-cell interactions, germline transcripts (Iγ2a) necessary for switch recombination to IgG2a. Analysis of the ligand-receptor pairs that could be involved in this induction revealed that the expression of CD48 on B cells is crucial for the induction. NK cells from mice with targeted deletions of either the CD2 or the CD244 gene, both of which encode ligands for CD48, are compromised in their ability to induce B cell Iγ2a expression. Interestingly, although CD244 can bind to CD48 with a higher affinity, the ability of NK cells from CD244−/− mice to stimulate Iγ2a is not as compromised as NK cells from CD2−/− mice. Despite the difference between cell surface receptors that are stimulated by NK cells vs those stimulated by the combination of LPS and IFN-γ, we show in this study that the initiation of γ2a germline transcription is regulated by similar cis-acting elements located at the 3′ end of the IgH locus. However, NK cells cannot induce the final steps of switch recombination resulting in the production of mature mRNA from recombined DNA. Our findings suggest that these different signaling pathways converge on regulatory elements that are common to germline transcription; however, because NK induction does not result in the final steps of switch recombination, some signals initiated by LPS plus IFN-γ are not induced by NK cells.

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“…The NK cells were fractioned by a 7-step Percoll gradient and negative selection methods as previously reported. 37 Purity of the enriched NK cell population was determined using flow cytometry by labeling the cells with fluorochrome-conjugated anti-CD3, -CD14, -CD19, and -CD56 antibodies (Abs) as described previously. The enriched NK cell population of a typical experiment was more than 85% CD56 ϩ , less than 5% CD3 ϩ , and less than 1% CD14 ϩ and CD19 ϩ .…”

Section: Cells and Reagentsmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-γ and its ligands attenuate biologic functions of human natural killer cells

Zhang

Rodríguez-Galán

Subleski

et al. 2004

Blood

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Interferon-␥ (IFN-␥) production and cytolytic activity are 2 major biologic functions of natural killer (NK) cells that are important for innate immunity. We demonstrate here that these functions are compromised in human NK cells treated with peroxisome proliferator-activated-␥ (PPAR-␥) ligands via both PPAR-␥-dependent and -independent pathways due to variation in PPAR-␥ expression. In PPAR-␥-null NK cells, 15-deoxy-⌬ 12,14 prostaglandin J 2 (15d-PGJ 2 ), a natural PPAR-␥ ligand, reduces IFN-␥ production that can be reversed by MG132 and/or chloroquine, and it inhibits cytolytic activity of NK cells through reduction of both conjugate formation and CD69 expression. In PPAR␥-positive NK cells, PPAR-␥ activation by 15d-PGJ 2 and ciglitazone (a synthetic ligand) leads to reduction in both mRNA and protein levels of IFN-␥. Overexpression of PPAR-␥ in PPAR-␥-null NK cells reduces IFN-␥ gene expression. However, PPAR-␥ expression and activation has no effect on NK cell cytolytic activity. In addition, 15d-PGJ 2 but not ciglitazone reduces expression of CD69 in human NK cells, whereas CD44 expression is not affected. These results reveal novel pathways regulating NK cell biologic functions and provide a basis for the design of therapeutic agents that can regulate the function of NK cells within the innate immune response. IntroductionNatural killer (NK) cells are bone marrow-derived cytotoxic lymphocytes with a granular morphology and account for up to 15% of peripheral blood lymphocytes. 1,2 They are important cellular components of innate immune defense against infection and immune surveillance against malignancies and transplanted organs. 3,4 NK cells are also implicated in the regulation of hematopoiesis and adaptive immune responses. 2,5 The biologic activity of NK cells includes not only cytokine production (eg, interferon-␥ [IFN-␥]) to regulate the type 1 T-cell immune response but also cytolytic activity, because NK cells can destroy target cells prior to sensitization and without restriction by major histocompatibility complex (MHC) antigens (natural killing activity). Imbalance of NK biologic functions has been implicated in the pathogenesis of autoimmune diseases such as diabetes. 6 Removal of NK cells abrogates cyclophosphamide-induced diabetes in nonobese diabetic (NOD) mice and prevents streptozotocin-induced diabetes in CD-1 mice. 7,8 Furthermore, IFN-␥ promotes the penetration of diabetogenic cells into pancreatic islets, and depletion of IFN-␥ delays the development of autoimmune diabetes in NOD mice. 9,10 Whereas the role of NK cells in pathogenesis has been extensively studied, the mechanisms involved in the regulation of NK functions remain to be defined. Many agents like cytokines, prostaglandins, and drugs regulate NK cell function. Interleukin-2 (IL-2) enhances intrinsic killing activity of NK cells and also induces a rapid expression of In contrast, interleukin-4 (IL-4) inhibits IFN-␥ production by human NK cells and regulates growth factor-dependent proliferation and differentiation of thes...

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Human B Cell Activation by Autologous NK Cells Is Regulated by CD40-CD40 Ligand Interaction: Role of Memory B Cells and CD5+ B Cells

Cited by 89 publications

References 46 publications

Tumor Cells Engineered with IL-12 and IL-15 Genes Induce Protective Antibody Responses in Nude Mice

Tumor Cells Engineered with IL-12 and IL-15 Genes Induce Protective Antibody Responses in Nude Mice

Receptors and Counterreceptors Involved in NK-B Cell Interactions

Peroxisome proliferator-activated receptor-γ and its ligands attenuate biologic functions of human natural killer cells

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