Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase

Gigoux, Mathieu; Shang, Jijun; Pak, Youngshil; Xu, Mengting; Choe, Jongseon; Mak, Tak W.; Suh, Woong‐Kyung

doi:10.1073/pnas.0911573106

Cited by 212 publications

(277 citation statements)

References 50 publications

(68 reference statements)

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“…Our data demonstrate that the strength of CD28 signaling in vivo translates directly into the level of ICOS surface expression induced on the T cell. This provides an elegant mechanism linking CD28 engagement to the ICOS-dependent activation of PI3K known to be critical for the generation of T FH s (61,62). Thus, neither CD28 nor ICOS alone is sufficient to induce the T FH program, consistent with microarray data obtained following independent engagement of these receptors (63).…”

Section: Discussionsupporting

confidence: 72%

“…The functionally relevant targets of the miR-17-92 cluster are still unclear, but the mechanism of action is likely to include direct and indirect repression of genes that antagonize T FH differentiation. Control of genes that regulate the PI3K pathway (e.g., the PI3K antagonist PTEN and the AKT phosphatase PHLPP2) may be particularly important (17,18), consistent with the well-recognized role of PI3K in the GC response (61,62).…”

Section: Discussionmentioning

confidence: 90%

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CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement

Wang

Heuts

Ovcinnikovs

et al. 2014

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

154

151

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Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an essential regulator of T-cell responses, and its absence precipitates lethal T-cell hyperactivity. However, whether CTLA-4 acts simply to veto the activation of certain clones or plays a more nuanced role in shaping the quality of T-cell responses is not clear. Here we report that T cells in CTLA-4-deficient mice show spontaneous Tfollicular helper (T FH ) differentiation in vivo, and this is accompanied by the appearance of large germinal centers (GCs). Remarkably, short-term blockade with anti-CTLA-4 antibody in wild-type mice is sufficient to elicit T FH generation and GC development. The latter occurs in a CD28-dependent manner, consistent with the known role of CTLA-4 in regulating the CD28 pathway. CTLA-4 can act by down-regulating CD80 and CD86 on antigen presenting cells (APCs), thereby altering the level of CD28 engagement. To mimic reduced CD28 ligation, we used mice heterozygous for CD28, revealing that the magnitude of CD28 engagement is tightly linked to the propensity for T FH differentiation. In contrast, other parameters of T-cell activation, including CD62L down-regulation and Ki67 expression, were relatively insensitive to altered CD28 level. Altered T FH generation as a result of graded reduction in CD28 was associated with decreased numbers of GC B cells and a reduction in overall GC size. These data support a model in which CTLA-4 control of immunity goes beyond vetoing T-cell priming and encompasses the regulation of T FH differentiation by graded control of CD28 engagement.ontrol of the magnitude and nature of adaptive immune responses is critical for health. The cytotoxic T-lymphocyteassociated antigen-4 (CTLA-4)/CD28 axis has long been known to control the magnitude of T-cell responses, however whether it also influences their nature has not been clear. Early studies suggested that CD28 may be particularly important for Th2 differentiation (1, 2), although others identified roles for CD28 in both Th1 and Th2 responses (3, 4). It is known that CD28 is an absolute requirement for the differentiation of follicular helper T cells (T FH s) that support germinal center (GC) formation (5, 6). However, these studies generally make use of CD28-deficient T cells, and therefore, results may reflect a failure of the cells to properly activate, proliferate, or survive, particularly given the known contribution of CD28 to these processes.A key outstanding question is whether CD28 costimulation in vivo is more complex than a binary checkpoint for T-cell priming. It is clear that expression of costimulatory ligands on antigen presenting cells (APCs) fluctuates in response to environmental stimuli, being up-regulated by inflammatory cytokines and TLR agonists and down-regulated by Treg-expressed CTLA-4 (7-11). Thus, variable levels of costimulatory ligands will be available for CD28 binding depending on the microenvironmental context. However, whether this simply alters the number of T cells that achieve the required threshold to commit to a resp...

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 90%

CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement

Wang

Heuts

Ovcinnikovs

et al. 2014

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

154

151

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“…Although we cannot exclude that the ICOS/ICOSL pathway is necessary for activation and homeostasis of diabetogenic T cells, we have to take into account the role of ICOS and ICOSL in T-celldependent B-cell responses [22,[24][25][26]. The ICOS/ICOSL pathway is indeed critical for isotypic commutation and somatic mutation in B cells.…”

Section: Discussionmentioning

confidence: 99%

Abrogation of ICOS/ICOS ligand costimulation in NOD mice results in autoimmune deviation toward the neuromuscular system

et al. 2010

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NOD mice spontaneously develop insulin-dependent diabetes around 10-40 wk of age. Numerous immune gene variants contribute to the autoimmune process. However, genes that direct the autoimmune response toward b cells remain ill defined. In this study, we provide evidence that the Icos and Icosl genes contribute to the diabetes process. Protection from diabetes in ICOS À/À and ICOSL À/À NOD mice was unexpectedly associated with the development of an autoimmune disorder of the neuro-muscular system, characterized by myositis, sensory ganglionitis and, to a reduced extent, inflammatory infiltrates in the CNS. This syndrome was reproduced upon adoptive transfer of CD4 1 and CD8 1T cells from diseased donors to naïve NOD.scid recipients. Our data further show that protection from diabetes results from defective activation of autoimmune diabetogenic effector T cells in ICOS À/À NOD mice, whereas acceleration of diabetes in BDC2.5 ICOS À/À NOD mice is induced by a dominant defect in Treg. Taken together, our findings indicate that costimulation signals play a key role in regulating immune tolerance in peripheral tissues and that the ICOS/ICOSL costimulatory pathway influences the balance between Treg and diabetogenic effector T cells.

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“…ICOS signaling (31). Interestingly, inclusion of a TLR9 ligand in the antigen resulted in substantially decreased IL-4 mRNA and increased IFN-γ mRNA (Fig.…”

Section: Tlr9mentioning

confidence: 99%

Toll-like receptor 9 signaling acts on multiple elements of the germinal center to enhance antibody responses

Rookhuizen

DeFranco

2014

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

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Recent studies have demonstrated important roles of nucleic acidsensing Toll-like receptors (TLRs) in promoting protective antibody responses against several viruses. To dissect how recognition of nucleic acids by TLRs enhances germinal center (GC) responses, mice selectively deleted for myeloid differentiation primaryresponse protein 88 (MyD88) in B cells or dendritic cells (DCs) were immunized with a haptenated protein antigen bound to a TLR9 ligand. TLR9 signaling in DCs led to greater numbers of follicular helper T (T FH ) cells and GC B cells, and accelerated production of broad-affinity antihapten IgG. In addition to modulating GC selection by increasing inducible costimulator (ICOS) expression on T FH cells and reducing the number of follicular regulatory T cells, MyD88-dependent signaling in B cells enhanced GC output by augmenting a class switch to IgG2a, affinity maturation, and the memory antibody response. Thus, attachment of a TLR9 ligand to an oligovalent antigen acted on DCs and B cells to coordinate changes in the T-cell compartment and also promoted B cell-intrinsic effects that ultimately programmed a more potent GC response.T he ability of the innate immune system to survey infection relies on pattern recognition receptors, such as Toll-like receptors (TLRs), that signal through myeloid differentiation primary-response protein 88 (MyD88) upon recognition of pathogen-associated molecular patterns (PAMPs). Recognition of infection by TLRs shapes adaptive immunity by directing dendritic cells (DCs) to activate naive T cells (1-3), by directing T helper (T H ) 1 and T H 17 polarization of effector T cells (3, 4), and by promoting B-cell activation and terminal differentiation to antibody-secreting plasma cells (5, 6).Following infection or vaccination, antibody responses generally proceed in two phases: an initial extrafollicular response, which rapidly generates short-lived plasmablasts that secrete low-affinity IgM and small quantities of isotype-switched antibodies (7), and a slower germinal center (GC) response, where B cells switch Ig isotype, increase affinity for antigen through somatic mutation of IgH and IgL genes, and undergo selection processes (8). Importantly, the GC builds protection from reinfection by selecting long-lived plasma cells and memory B cells from cells expressing isotype-switched, affinity-matured Bcell antigen receptors (BCRs) (9). Initially, it was proposed that TLR signaling selectively favored the extrafollicular component of serological immunity (10), but it was shown subsequently that TLR signaling in B cells could greatly augment the GC response to virus-like particles, nanoparticles, and virions (5,11,12). Moreover, the ability of B-cell TLRs to enhance the antibody response was recently shown to be important for host defense of mice infected with Friend virus and the chronic version of lymphocytic choriomeningitis virus (LCMV) (12)(13)(14).Follicular helper T (T FH ) cells maintain the GC and govern selection for GC B cells with increased affinity for antigen (...

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Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase

Cited by 212 publications

References 50 publications

CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement

CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement

Abrogation of ICOS/ICOS ligand costimulation in NOD mice results in autoimmune deviation toward the neuromuscular system

Toll-like receptor 9 signaling acts on multiple elements of the germinal center to enhance antibody responses

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