SAP-controlled T–B cell interactions underlie germinal centre formation

Qi, Hai; Cannons, Jennifer L.; Klauschen, Frederick; Schwartzberg, Pamela L.; Germain, Ronald N.

doi:10.1038/nature07345

Cited by 549 publications

(726 citation statements)

References 45 publications

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“…Recent studies have also suggested the requirement of stable DC:T cell interactions for the induction of immunity, rather than tolerance (15,(20)(21)(22). Strikingly, recent publications suggest that peptide:class II complexes that persist for long periods of time may be an essential feature of a germinal center reaction (23,24). All these studies are consistent with the possibility that peptides that have long-lived interactions with class II may have a selective advantage during competitive CD4 T cell priming in vivo.…”

supporting

confidence: 74%

“…1A). Strikingly, however, when the expansion of HEL [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]-specific T cells was monitored after coadministration with several high-stability dominant peptides, there was a dramatic loss in the number of T cells detected. To verify this important finding, a peptide from OVA, for which several peptide variants of altered kinetic stabilities with class II have been defined (1) and known priming doses so they are loaded at similar initial epitope densities (Fig.…”

Section: Peptides With Fast Off-rates From Class II Elicit Diminishedmentioning

confidence: 99%

“…CD4 T cell expansion is then evaluated by assessing the number of responding T cells at the peak of the immune response via IL-2 ELISpot assays. All peptides were emulsified in IFA containing LPS as an adjuvant.Initial studies used the well-defined, cryptic peptide HEL [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25], which has very unstable interactions with I-A d (t 1/2 12 h). When…”

mentioning

confidence: 99%

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Abortive activation of CD4 T cell responses during competitive priming in vivo

Weaver

Chaves

Sant

2009

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

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Immunodominance refers to the highly selective peptide reactivity of T cells during an immune response. In this study, we tested the hypothesis that persistence of peptide:class II complexes is one key parameter that selects the final specificity of CD4 T cells. We found that low-stability peptide:class II complexes support the initial priming and expansion of CD4 T cells, but the expansion becomes strikingly aborted in the presence of competitive T cell responses to unrelated peptides. Our experiments revealed that for inhibition to occur, the competitive responses must be initiated by the same antigen presenting cell, and it is not because of competition for MHC binding. These studies not only provide an insight into the events that regulate competitive CD4 T cell priming in vivo, but also provide a previously undescribed conceptual framework to understand the parameters that select the final specificity of the T cell repertoire during pathogen or vaccine-induced immune responses.A ntigen presenting cells (APC) ingest antigens in peripheral tissues and, in response to inflammatory signals, migrate to lymph nodes (LNs), where they present peptide antigens bound to MHC class II molecules to recirculating CD4 T cells. The majority of T cells that are primed during an immune response are selectively skewed to one or a few of the many possible peptides from an antigen, resulting in a phenomenon known as immunodominance. Our laboratory has shown that an intrinsic biochemical property of the ligand recognized by the responding T cells, the kinetic stability of the peptide:MHC class II complexes, has the major role in both predicting and determining immunodominance (1). High-stability peptides elicit dominant responses, whereas low-stability peptides do not recruit detectable responses and are thus, ''cryptic'' (1). Selectivity in the repertoire of the presented peptide:class II complexes was shown to be modulated by DM editing in APC (2-4), and to be independent of the protein context in which those peptides resided (5).Recent findings describing the dynamic interactions of antigenbearing dendritic cells (DC) and T cells suggest that peptide off-rates from class II molecules may impact the immune response (6-8). The quality of signals received through the T cell antigen receptor (TcR) by peptides of different affinity for MHC class II has recently been suggested to regulate the fate and function of CD4 T cells (9, 10). Despite new methods that allow visualization of different phases of DC:T cell interactions to antigenic stimulus in vivo (11-18), the factors that contribute to efficient T cell activation and how the kinetic features of those interactions governs the fate of the responding T cells is still unknown. The decision for a T cell to ''stop'' and form long-lived contacts with a DC when scanning for cognate antigen may depend on multiple parameters, but antigen density (12) and peptide affinity for class II (19) have been shown to augment the frequency of prolonged DC:T cell contacts, increasing the efficienc...

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supporting

confidence: 74%

Section: Peptides With Fast Off-rates From Class II Elicit Diminishedmentioning

confidence: 99%

mentioning

confidence: 99%

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Abortive activation of CD4 T cell responses during competitive priming in vivo

Weaver

Chaves

Sant

2009

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

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“…Most GC Tfh cells have a CXCR5 hi , CCR7 lo , PSGL‐1 lo , programmed cell death protein 1 (PD‐1) hi phenotype and express high levels of Bcl6, Maf, and SLAM‐associated protein (SAP). SAP expression is essential for GC formation,135 preventing inhibitory signaling through SLAM family member 6 (SLAMF6) to enable Tfh‐B cell adhesion,136 which is crucial for Tfh cell retention in GCs and provision of help to B cells. Bcl6 plays a central role in Tfh cell differentiation,115, 137, 138 but other transcription factors that act upstream and downstream of Bcl6 are also required (reviewed in 139).…”

Section: T Follicular Helper Cells and Their Role In Bnab Inductionmentioning

confidence: 99%

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Borrow

Moody

2017

Immunological Reviews

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SummaryInduction of broadly neutralizing antibodies (bnAbs) capable of inhibiting infection with diverse variants of human immunodeficiency virus type 1 (HIV‐1) is a key, as‐yet‐unachieved goal of prophylactic HIV‐1 vaccine strategies. However, some HIV‐infected individuals develop bnAbs after approximately 2‐4 years of infection, enabling analysis of features of these antibodies and the immunological environment that enables their induction. Distinct subsets of CD4+ T cells play opposing roles in the regulation of humoral responses: T follicular helper (Tfh) cells support germinal center formation and provide help for affinity maturation and the development of memory B cells and plasma cells, while regulatory CD4+ (Treg) cells including T follicular regulatory (Tfr) cells inhibit the germinal center reaction to limit autoantibody production. BnAbs exhibit high somatic mutation frequencies, long third heavy‐chain complementarity determining regions, and/or autoreactivity, suggesting that bnAb generation is likely to be highly dependent on the activity of CD4+ Tfh cells, and may be constrained by host tolerance controls. This review discusses what is known about the immunological environment during HIV‐1 infection, in particular alterations in CD4+ Tfh, Treg, and Tfr populations and autoantibody generation, and how this is related to bnAb development, and considers the implications for HIV‐1 vaccine design.

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“…The first step towards GC formation is activation of naïve B cells by exogenous T-cell dependent antigen in the follicles of peripheral lymphoid tissues. Next, antigen-engaged B-cells migrate to the border between the follicles and the T cell zone or interfollicular zones, where they undergo proliferation and interact with cognate Tfh cells within 1-3 days after stimulation [18][19][20][21]. B-cells can then differentiate into extrafollicular plasma cells and leave the follicle to generate low-affinity antibodies, or alternatively can enter the GC pathway [22].…”

Section: Gc B Cell Development and B Cell Lymphomagenesismentioning

confidence: 99%

Mechanisms of action of BCL6 during germinal center B cell development

Huang

Melnick

2015

Sci. China Life Sci.

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The transcriptional repressor B cell lymphoma 6 (BCL6) controls a large transcriptional network that is required for the formation and maintenance of germinal centers (GC). GC B cells represent the normal counterpart of most human B-cell lymphomas, which are often characterized by deregulated BCL6 expression or BCL6-mediated pathways. BCL6 suppresses gene transcription largely through recruitment of its co-repressors through its distinct repression domain. Understanding the precise biological roles of each repression domain in normal and malignant B cells is helpful for development of targeted inhibition of BCL6 functions that is emerging as the basis for design of anti-lymphoma therapies. This review focuses on recent progress in the molecular mechanisms of action of BCL6 in B cells and discusses remaining unresolved questions related to how these mechanisms are linked to normal and malignant B cell development. BCL6, germinal center, co-repressor, lymphoma Citation:Huang CX, Melnick A. Mechanisms of action of BCL6 during germinal center B cell development.

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SAP-controlled T–B cell interactions underlie germinal centre formation

Cited by 549 publications

References 45 publications

Abortive activation of CD4 T cell responses during competitive priming in vivo

Abortive activation of CD4 T cell responses during competitive priming in vivo

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Mechanisms of action of BCL6 during germinal center B cell development

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