Arrest of B Lymphocyte Terminal Differentiation by CD40 Signaling: Mechanism for Lack of Antibody-Secreting Cells in Germinal Centers

Although it is well-known that the ICOS-ICOS ligand (ICOSL) costimulatory pathway is important for many immune responses, recent accumulated evidence suggests that dysregulation of this pathway may lead to and/or exaggerate autoimmune responses. ICOS is induced on the cell surface after T cell activation. Similarly, ICOSL is up-regulated on APCs by several mitogenic stimuli. However, the mechanism regulating expression of the ICOS-ICOSL pair, and the significance of controlling their expression for an appropriate immune response, is largely unknown. To gain a better understanding of the importance of fine control of the ICOS-ICOSL costimulatory pathway, we generated ICOS-transgenic (Tg) mice that have high constitutive expression of ICOS in all T cells. Using ICOS-Tg mice, we studied whether in vivo immune responses were affected. Unexpectedly, we first found that ICOS-Tg mice exhibited a phenotype resembling ICOS-deficient mice in their Ag-specific Ab response, such as a defect in class switch recombination. Further examination revealed that ICOSL expression of APCs was significantly suppressed in ICOS-Tg mice. Interestingly, suppression of ICOSL was induced by interaction of ICOSL with ICOS, and it seemed to be regulated at the posttranscriptional level. The suppressive effect of the ICOS-ICOSL interaction overcame the positive effect of CD40 or B cell activation factor of the TNF family (BAFF) stimulation on ICOSL expression. Together, our studies demonstrate a novel mechanism for the regulation of ICOSL expression in vivo and suggest that the ICOS costimulatory pathway is subject to negative feedback regulation by ICOSL down-regulation in response to ICOS expression.

Section: Discussionmentioning

confidence: 99%

Down-Regulation of ICOS Ligand by Interaction with ICOS Functions as a Regulatory Mechanism for Immune Responses

Watanabe

Takagi

Kotani³

et al. 2008

“…A number of experimental observations, including the immune deficiency disorder in humans associated with CD40L deficiency, have demonstrated the importance of CD40-CD40L in humoral immunity (6 -13, 15-17, 35-38). Initial studies focused on the role of CD40 signaling of the B cell following engagement with CD40L from the T helper cell (11)(12)(13)(14)(15)(16)(17). A number of in vitro experiments have demonstrated the impact of CD40 signaling of the B cell, in combination with cytokines, on several steps along the pathway of B cell response, such as proliferation and Ig secretion (12)(13)(14)(15)(16)(17).…”

Section: Discussionmentioning

confidence: 99%

“…Initial studies focused on the role of CD40 signaling of the B cell following engagement with CD40L from the T helper cell (11)(12)(13)(14)(15)(16)(17). A number of in vitro experiments have demonstrated the impact of CD40 signaling of the B cell, in combination with cytokines, on several steps along the pathway of B cell response, such as proliferation and Ig secretion (12)(13)(14)(15)(16)(17). Other more complex steps in B cell development, such as germinal center formation, somatic hypermutation, and creation of memory, clearly require CD40L-CD40, as demonstrated by murine models in which these pathways are inhibited by germline mutations, infusion of blocking Abs, or soluble receptors (12)(13)(14)(15)(16)(17).…”

Section: Discussionmentioning

confidence: 99%

“…The function of CD40 is best characterized in B cells, where it plays an essential role in T cell-dependent B cell responses (11). A number of in vitro and in vivo studies have implicated direct signaling of B cells by CD40 as a critical step at numerous stages of the B cell response including proliferation and clonal expansion, Ig production, germinal center formation, isotype switching, affinity maturation, and induction of B cell memory (12)(13)(14)(15)(16)(17). Experiments in animals deficient in CD40L or CD40 suggest that these molecules also play a primary role in CD4 ϩ T cell activation (18,19).…”

mentioning

confidence: 99%

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Th2-Dependent B Cell Responses in the Absence of CD40-CD40 Ligand Interactions

Chirmule

Tazelaar

Wilson

2000

CD40 is thought to play a central role in T cell-dependent humoral responses through two distinct mechanisms. CD4+ T helper cells are activated via CD40-dependent Ag presentation in which CD80/CD86 provides costimulation through CD28. In addition, engagement of CD40 on B cells provides a direct pathway for activation of humoral responses. We used a model of adenovirus-mediated gene transfer of β-galactosidase (lacZ) into murine lung to evaluate the specific CD40-dependent pathways required for humoral immunity at mucosal surfaces of the lung. Animals deficient in CD40L failed to develop T and B cell responses to vector. Activation of Th2 cells, which normally requires CD40-dependent stimulation of APCs, was selectively reconstituted in CD40 ligand-deficient mice by systemic administration of an Ab that is agonistic to CD28. Surprisingly, this resulted in the development of a functional humoral response to vector as evidenced by formation of germinal centers and production of antiadenovirus IgG1 and IgA that neutralized and prevented effective readministration of vector. The CD28-dependent B cell response required CD4+ T cells and was mediated via IL-4. These studies indicate that CD40 signals to the B cells are not necessary for CD4+ Th2 cell-dependent humoral responses to be generated.

“…10). However, it has been shown that continued CD40 signaling in activated B cells prevents terminal differentiation as measured by a decrease in both secretory Ig and the transcriptional regulator B lymphocyte-induced maturation protein 1 (30). Together, these studies suggest that CD154 expression is critical for regulating the immune response at early and late times after activation.…”

Section: A Complex Containing Polypyrimidine Tract-binding Proteinmentioning

confidence: 95%

A Complex Containing Polypyrimidine Tract-Binding Protein Is Involved in Regulating the Stability of CD40 Ligand (CD154) mRNA

Kosinski

Laughlin

Singh

et al. 2003

CD40 ligand (CD154) expression has been shown to be regulated, in part, at the posttranscriptional level by a pathway of “regulated instability” of mRNA decay throughout a time course of T cell activation. This pathway is modulated at late times of activation by the binding of a stability complex (termed complex I) to a CU-rich region in the 3′ untranslated region of the CD154 message. We have undertaken experiments to extend these findings and to analyze the cis-acting elements and trans-acting factors involved in this regulation. We have previously shown that the minimal binding sequence for complex I is a 63 nt CU-rich motif. However, our current study shows that when this site was deleted additional complex binding was observed upstream and downstream of the minimal binding region. Only after deletion of an extended region (termed Δ1515) was complex binding completely abolished. Analysis of complex binding using competition experiments revealed that the three adjacent regions bound related but not identical complexes. However, all three sites appeared to have a 55-kDa protein as the RNA-binding protein. Deletion of the Δ1515 region resulted in reduced transcript stability as measured by both in vitro and in vivo decay assays. Finally, using Abs against known RNA-binding proteins, we identified the polypyrimidine tract-binding protein (or heterogeneous nuclear ribonucleoprotein I) as a candidate RNA-binding component of complex I.