Characterization of Human Inducible Costimulator Ligand Expression and Function

Aicher, Alexandra; Hayden-Ledbetter, Martha; Brady, William; Pezzutto, Antonio; Richter, G.; Magaletti, Dario M.; Buckwalter, Sonya; Ledbetter, Jeffrey A.; Clark, Edward A.

doi:10.4049/jimmunol.164.9.4689

Cited by 223 publications

(174 citation statements)

References 38 publications

(23 reference statements)

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“…1B). Although some suggest that ERK is activated downstream of CD40 in B cells (7), others have suggested that this may not be the case (4,5) or that CD40-induced ERK activation may be more prominent in monocytic cells than in B cells (51). Our results, based on early gene expression, agree with the latter hypothesis.…”

Section: Discussionsupporting

confidence: 82%

Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes

Dadgostar

Zarnegar

Hoffmann

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

110

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CD40͞CD40L interaction is essential for multiple biological events in T dependent humoral immune responses, including B cell survival and proliferation, germinal center and memory B cell formation, and antibody isotype switching and affinity maturation. By using high-density microarrays, we examined gene expression in primary mouse B lymphocytes after multiple time points of CD40L stimulation. In addition to genes involved in cell survival and growth, which are also induced by other mitogens such as lipopolysaccharide, CD40L specifically activated genes involved in germinal center formation and T cell costimulatory molecules that facilitate T dependent humoral immunity. Next, by examining the roles of individual CD40-activated signal transduction pathways, we dissected the overall CD40-mediated response into genes independently regulated by the individual pathways or collectively by all pathways. We also found that gene down-regulation is a significant part of the overall response and that the p38 pathway plays an important role in this process, whereas the NF-B pathway is important for the up-regulation of primary response genes. Our finding of overlapping independent control of gene expression modules by different pathways suggests, in principle, that distinct biological behaviors that depend on distinct gene expression subsets can be manipulated by targeting specific signaling pathways. C D40 is a member of the pleiotropic tumor necrosis factor receptor (TNFR) superfamily, which also includes such functionally diverse molecules as CD27, CD30, OX40, RANK, LT-␤R, the p75 low-affinity nerve growth factor receptor, Fas, and members of the death receptor family as well as TNFR1 and TNFR2 (1). CD40 stimulation activates B cells and promotes various aspects of a functional humoral immune response, including enhancement of survival and proliferation (2). Like many TNFR family members, CD40 activates the JNK͞SAPK and NF-B pathways (3, 4). Both of these pathways involve serine͞threonine kinases that regulate gene expression through activation of AP1 and Rel transcription factors, respectively. Another stress-responsive pathway that has also been reported to be activated by CD40 (5) is the p38 kinase pathway, which leads to the phosphorylation and activation of transcription factors such as ATF2 (6). Previous work has also linked CD40 to the activation of the extracellular signal-regulated kinase (ERK)͞mitogen-activated protein kinase (MAPK) pathway (7).In addition to serine͞threonine kinases, a link between CD40 signaling and tyrosine kinase activation has been suggested (8).One pathway shown to be activated by CD40 and to play an important role in CD40 signaling is that initiated by PI-3 kinase (PI-3K) (8-10). PI-3K phosphorylates membrane phospholipids (11), which can recruit and activate pleckstrin homology domaincontaining molecules such as the kinase protein kinase B. This kinase may then regulate the activity of forkhead-related transcription factors (12, 13).In each of the above pathways, one of the major final ...

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Section: Discussionsupporting

confidence: 82%

Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes

Dadgostar

Zarnegar

Hoffmann

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

110

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“…Furthermore, there is evidence that PD-L1: PD-1 interactions may influence alloreactive T cell responses by inducing regulatory cells, and that blocking of PD-L1, but not PD-L2 signaling, prevents their induction (52). Interestingly, ICOSL expression, that was observed at comparatively low levels on both AADC and control GMDC in the present study, is not (unlike CD80 and CD86) dependent on NF-B activation (53).…”

Section: Discussionmentioning

confidence: 48%

“Alternatively Activated” Dendritic Cells Preferentially Secrete IL-10, Expand Foxp3+CD4+ T Cells, and Induce Long-Term Organ Allograft Survival in Combination with CTLA4-Ig

Lan

Wang²,

Raimondi³

et al. 2006

The Journal of Immunology

147

139

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In this study, we propagated myeloid dendritic cells (DC) from BALB/c (H2d) mouse bone marrow progenitors in IL-10 and TGF-β, then stimulated the cells with LPS. These “alternatively activated” (AA) DC expressed lower TLR4 transcripts than LPS-stimulated control DC and were resistant to maturation. They expressed comparatively low levels of surface MHC class II, CD40, CD80, CD86, and programmed death-ligand 2 (B7-DC; CD273), whereas programmed death-ligand 1 (B7-H1; CD274) and inducible costimulatory ligand expression were unaffected. AADC secreted much higher levels of IL-10, but lower levels of IL-12p70 compared with activated control DC. Their poor allogeneic (C57BL/10; B10) T cell stimulatory activity and ability to induce alloantigen-specific, hyporesponsive T cell proliferation was not associated with enhanced T cell apoptosis. Increased IL-10 production was induced in the alloreactive T cell population, wherein CD4+Foxp3+ cells were expanded. The AADC-expanded allogeneic CD4+CD25+ T cells showed enhanced suppressive activity for T cell proliferative responses compared with freshly isolated T regulatory cells. In vivo migration of AADC to secondary lymphoid tissue was not impaired. A single infusion of BALB/c AADC to quiescent B10 recipients induced alloantigen-specific hyporesponsive T cell proliferation and prolonged subsequent heart graft survival. This effect was potentiated markedly by CTLA4-Ig, administered 1 day after the AADC. Transfer of CD4+ T cells from recipients of long-surviving grafts (>100 days) that were infiltrated with CD4+Foxp3+ cells, prolonged the survival of donor-strain hearts in naive recipients. These data enhance insight into the regulatory properties of AADC and demonstrate their therapeutic potential in vascularized organ transplantation.

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“…This could suggest the convergence or competition of LIGHT and CD40L signaling for Ig secretion for a limiting step that, thus, could not be modified by additional stimulation. In addition to stimulation by TNF/TNFR family members, interaction of ICOS [4], which is a member of the B7 family of costimulatory molecules, with its ligand [5] has also an important role in B cell physiology. ICOS is expressed on both CD4 + and CD8 + activated T lymphocytes [6].…”

Section: Light Stimulation Enhances Ig Secretionmentioning

confidence: 99%

LIGHT costimulates CD40 triggering and induces immunoglobulin secretion; a novel key partner in T cell‐dependent B cell terminal differentiation

et al. 2004

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The T cell-dependent differentiation and function of B lymphocytes are tightly regulated by TNF ligands (L) and receptors interactions, such as CD40/CD40L, CD27/CD70 and CD134/ CD314L. The LIGHT/HVEM system [homologous to lymphotoxin, inducible expression, competing for GpD of herpes virus, that binds to the herpes virus entry mediator (HVEM), and is expressed on activated T lymphocytes) focused our attention since HVEM has a large distribution that, in addition to T cells, DC or NK, includes tumor and normal B lymphocytes. HVEM was expressed on memory and naive B cells from peripheral blood or tonsils, but not on germinal center (GC) B cells. Costimulation by CD40L+LIGHT induced LIGHT expression at the B lymphocyte surface by a transcriptional mechanism since we detected de novo expression of LIGHT-specific mRNA. LIGHTexpression was further enhanced by triggering of surface IgM, a stimulus that mimics a normal step of B cell physiology, i.e. specific antigen encounter. Stimulation by LIGHT increased the B cell proliferation induced by CD40L, and induced IgG and IgM (but not IgA) secretion. We conclude that LIGHT costimulation, that mimics the B cell encounter with activated LIGHT-expressing T lymphocytes, enhances both B cell proliferation and Ig production, and thus has a central importance for humoral immunity development.

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Characterization of Human Inducible Costimulator Ligand Expression and Function

Cited by 223 publications

References 38 publications

Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes

Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes

“Alternatively Activated” Dendritic Cells Preferentially Secrete IL-10, Expand Foxp3+CD4+ T Cells, and Induce Long-Term Organ Allograft Survival in Combination with CTLA4-Ig

LIGHT costimulates CD40 triggering and induces immunoglobulin secretion; a novel key partner in T cell‐dependent B cell terminal differentiation

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