B Cell-Specific Expression of B7-2 Is Required for Follicular Th Cell Function in Response to Vaccinia Virus

Salek‐Ardakani, Samira; Choi, Youn Soo; Benhnia, Mohammed Rafii‐El‐Idrissi; Flynn, Rachel; Arens, Ramon; Shoenberger, Stephen; Crotty, Shane; Croft, Michael; Salek-Ardakani, Shahram

doi:10.4049/jimmunol.1100406

Cited by 67 publications

(67 citation statements)

References 42 publications

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“…Thus, the absence of circulating Tfh cells in patients with two TACI mutations may illustrate dysfunctional GC reactions and decreased isotype-switched antibody secretion. In agreement with this hypothesis, murine models have demonstrated that either CD86 or ICOSL deficiency abolish GC formation and impair the generation of Tfh cells (50)(51)(52). However, expanded Tfh cells driven by overexpression of ICOSL on B cells have been reported in Taci knockout mice (53).…”

Section: Methodsmentioning

confidence: 67%

CVID-associated TACI mutations affect autoreactive B cell selection and activation

Romberg¹,

Chamberlain²,

Saadoun³

et al. 2013

J. Clin. Invest.

152

198

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Common variable immune deficiency (CVID) is an assorted group of primary diseases that clinically manifest with antibody deficiency, infection susceptibility, and autoimmunity. Heterozygous mutations in the gene encoding the tumor necrosis factor receptor superfamily member TACI are associated with CVID and autoimmune manifestations, whereas two mutated alleles prevent autoimmunity. To assess how the number of TACI mutations affects B cell activation and tolerance checkpoints, we analyzed healthy individuals and CVID patients carrying one or two TACI mutations. We found that TACI interacts with the cleaved, mature forms of TLR7 and TLR9 and plays an important role during B cell activation and the central removal of autoreactive B cells in healthy donors and CVID patients. However, only subjects with a single TACI mutation displayed a breached immune tolerance and secreted antinuclear antibodies (ANAs). These antibodies were associated with the presence of circulating B cell lymphoma 6-expressing T follicular helper (Tfh) cells, likely stimulating autoreactive B cells. Thus, TACI mutations may favor CVID by altering B cell activation with coincident impairment of central B cell tolerance, whereas residual B cell responsiveness in patients with one, but not two, TACI mutations enables autoimmune complications.

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Section: Methodsmentioning

confidence: 67%

CVID-associated TACI mutations affect autoreactive B cell selection and activation

Romberg¹,

Chamberlain²,

Saadoun³

et al. 2013

J. Clin. Invest.

152

198

View full text Add to dashboard Cite

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“…Indeed, pre-T FH /B cell interactions appear sufficient in early life as adults to initiate T FH cell differentiation (9,35), T cell entry into the follicle, and Bcl6 upregulation (6), but not for GC T FH cell expansion/maintenance. This last stage is known to imply additional requirements, including the SLAM family of receptors and the SLAM-associated proteins required for the formation of sufficiently stable T-B conjugates for T FH cell-GC B cell signaling (27,36,37), sufficient CD80/CD86-CD28 and CD40-CD40L signals to sustain TCR activation (38)(39)(40), and numerous specific GC T FH cell differentiation signals. Neonatal B cells are known for their reduced strength of BCR signaling and lower levels of costimulatory receptors (including CD21, CD40, CD80, and CD86) (3), which could limit their interactions even with functionally competent adoptively transferred adult T FH cells.…”

Section: Discussionmentioning

confidence: 99%

Environmental and T Cell–Intrinsic Factors Limit the Expansion of Neonatal Follicular T Helper Cells but May Be Circumvented by Specific Adjuvants

Mastelic

Kamath

Fontannaz

et al. 2012

The Journal of Immunology

102

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Follicular Th (TFH) cells have emerged as a new Th subset providing help to B cells and supporting their differentiation into long-lived plasma cells or memory B cells. Their differentiation had not yet been investigated following neonatal immunization, which elicits delayed and limited germinal center (GC) responses. We demonstrate that neonatal immunization induces CXCR5highPD-1high CD4+ TFH cells that exhibit TFH features (including Batf, Bcl6, c-Maf, ICOS, and IL-21 expression) and are able to migrate into the GCs. However, neonatal TFH cells fail to expand and to acquire a full-blown GC TFH phenotype, as reflected by a higher ratio of GC TFH/non-GC CD4+ T cells in immunized adults than neonates (3.8 × 10−3 versus 2.2 × 10−3, p = 0.01). Following the adoptive transfer of naive adult OT-II CD4+ T cells, OT-II TFH cells expand in the vaccine-draining lymph nodes of immunized adult but not infant recipients, whereas naive 2-wk-old CD4+ OT-II cells failed to expand in adult hosts, reflecting the influence of both environmental and T cell–intrinsic factors. Postponing immunization to later in life increases the number of TFH cells in a stepwise manner, in direct correlation with the numbers of GC B cells and plasma cells elicited. Remarkably, adjuvantation with CpG oligonucleotides markedly increased GC TFH and GC B cell neonatal responses, up to adult levels. To our knowledge, this is the first demonstration that the TFH cell development limits early life GC responses and that adjuvants/delivery systems supporting TFH differentiation may restore adultlike early life GC B cell responses.

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“…Given the sequential interaction of T cells with dendritic cells (DCs) and B cells during humoral responses, this could reflect distinct cell type-specific or kinetic expression patterns between ligands. Of note, studies have documented the importance of either CD86 (52) or CD80 (53) on B cells for T FH generation and GC responses. It is possible that the nature and context of the antigenic challenge dictate the relative requirement for CD80 versus CD86, consistent with the capacity of strong adjuvants to restore the GC response in CD86 −/− mice (65).…”

Section: Discussionmentioning

confidence: 99%

“…The simplest explanation for the capacity of T FR to control GC size is that they limit T FH number and thereby restrict the ability of T cells to rescue GC B cells from death. Because T FH homeostasis is tightly linked to the availability of costimulatory ligands on B cells (52,53), it is easy to envisage how T FR could use the CTLA-4 pathway to control T FH by downregulating costimulatory ligand expression on B cells.…”

Section: Discussionmentioning

confidence: 99%

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.

159

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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B Cell-Specific Expression of B7-2 Is Required for Follicular Th Cell Function in Response to Vaccinia Virus

Cited by 67 publications

References 42 publications

CVID-associated TACI mutations affect autoreactive B cell selection and activation

CVID-associated TACI mutations affect autoreactive B cell selection and activation

Environmental and T Cell–Intrinsic Factors Limit the Expansion of Neonatal Follicular T Helper Cells but May Be Circumvented by Specific Adjuvants

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

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