Functional and Epigenetic Studies Reveal Multistep Differentiation and Plasticity of In Vitro-Generated and In Vivo-Derived Follicular T Helper Cells

Lu, Kristina T.; Kanno, Yuka; Cannons, Jennifer L.; Handon, Robin; Bible, Paul W.; Elkahloun, Abdel G.; Anderson, Stacie M.; Wei, Lai; Sun, Hongwei; O’Shea, John J.; Schwartzberg, Pamela L.

doi:10.1016/j.immuni.2011.07.015

Cited by 223 publications

(252 citation statements)

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“…5B). These data are consistent with reduced expansion of GC B cells in these mice because multiple observations suggest that T FH cell development is a limiting factor for the generation and expansion of GC B cells (35)(36)(37). In contrast, MyD88 deletion in B cells resulted in little or no reduction in total T FH cell numbers following CpG-NPCGG immunization (Fig.…”

Section: Tlr9-stimulated Dcs and B Cells Differentially Regulate T Fhsupporting

confidence: 87%

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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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Section: Tlr9-stimulated Dcs and B Cells Differentially Regulate T Fhsupporting

confidence: 87%

“…For example, adoptive transfer of WT in vitro-differentiated T FH -like cells into WT mice increased the magnitude of the GC response, indicating that the numbers of T FH cells can be limiting for GC reactions (35)(36)(37).…”

Section: Discussionmentioning

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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“…5a). However, their induction or co-expression in opposing subsets, especially with FOXP3, indicates that counter-regulation of their expression is incomplete 37,117 . Thus, these so-called master transcription factors behave less like lineage-definers and more like executors, expressed in response to environmental cues to carry out the induction of a defined set of gene effectors.…”

Section: Box 2 | Phenotypic Plasticity In Inflammatory and Regulatorymentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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| CD4 + T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4 + T cell plasticity by examining the molecular mechanisms that regulate it -from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

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“…44). CD4 + T-cell lineage commitment is determined by the cytokine composition of the microenvironment in which the CD4 + T cells are primed and boosted via transcriptional regulation of lineage-specific cytokine gene families (38,39,45). This observation leads to the sobering possibility that CD4 + CCR5 + T cells (i.e., Th17 cells) responding to an HIV vaccine designed to elicit a persistent and protective antibody response could blunt protection or, worse, increase susceptibility to infection, as suggested in the adenovirus serotype 5 (Ad5) vaccine trials (13)(14)(15)(16).…”

mentioning

confidence: 99%

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

Lewis

DeVico

Gallo

2014

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

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The quest for a prophylactic AIDS vaccine is ongoing, but it is now clear that the successful vaccine must elicit protective antibody responses. Accordingly, intense efforts are underway to identify immunogens that elicit these responses. Regardless of the mechanism of antibodymediated protection, be it neutralization, Fc-mediated effector function, or both, antibody persistence and appropriate T-cell help are significant problems confronting the development of a successful AIDS vaccine. Here, we discuss the evidence illustrating the poor persistence of antibody responses to Env, the envelope glycoprotein of HIV-1, and the related problem of CD4 + T-cell responses that compromise vaccine efficacy by creating excess cellular targets of HIV-1 infection. Finally, we propose solutions to both problems that are applicable to all Envbased AIDS vaccines regardless of the mechanism of antibody-mediated protection.

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Functional and Epigenetic Studies Reveal Multistep Differentiation and Plasticity of In Vitro-Generated and In Vivo-Derived Follicular T Helper Cells

Cited by 223 publications

References 57 publications

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

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

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

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