T cell help controls the speed of the cell cycle in germinal center B cells

Gitlin, Alexander D.; Mayer, Christian T.; Oliveira, Thiago Y.; Shulman, Ziv; Ma, Jones; Koren, Amnon; Nussenzweig, Michel C.

doi:10.1126/science.aac4919

Cited by 206 publications

(246 citation statements)

References 41 publications

(51 reference statements)

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“…Therefore, although we find Tfh cell and germinal center responses in BG505 SOSIP.664 trimer-immunized mice, if naive B cells of appropriate Tier-2-neutralizing epitope specificity do not exist in the repertoire, then Tfh cells will only be able to help the B cells of the nonneutralizing and Tier-1-neutralizing specificities. In contrast, in the context of other animal models (i.e., rabbits and macaques) that can elicit Tier-2 nAbs, Tfh cells may have a substantial impact on the generation of high-affinity Tier-2 nAbs given their role in GC B cell selection (89) and extent of somatic hypermutation per selection cycle (16,90). Thus, it will be important to continue understanding the role of Tfh cells in the generation of high-affinity Tier-2 nAbs and bnAbs.…”

Section: Discussionmentioning

confidence: 97%

Murine Antibody Responses to Cleaved Soluble HIV-1 Envelope Trimers Are Highly Restricted in Specificity

Crampton

Cupo

et al. 2015

J Virol

156

179

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Generating neutralizing antibodies (nAbs) is a major goal of many current HIV-1 vaccine efforts. To be of practical value, these nAbs must be both potent and cross-reactive in order to be capable of preventing the transmission of the highly diverse and generally neutralization resistant (Tier-2) HIV-1 strains that are in circulation. The HIV-1 envelope glycoprotein (Env) spike is the only target for nAbs. To explore whether Tier-2 nAbs can be induced by Env proteins, we immunized conventional mice with soluble BG505 SOSIP.664 trimers that mimic the native Env spike. Here, we report that it is extremely difficult for murine B cells to recognize the Env epitopes necessary for inducing Tier-2 nAbs. Thus, while trimer-immunized mice raised Env-binding IgG Abs and had high-quality T follicular helper (Tfh) cell and germinal center (GC) responses, they did not make BG505.T332N nAbs. Epitope mapping studies showed that Ab responses in mice were specific to areas near the base of the soluble trimer. These areas are not well shielded by glycans and likely are occluded on virions, which is consistent with the lack of BG505.T332N nAbs. These data inform immunogen design and suggest that it is useful to obscure nonneutralizing epitopes presented on the base of soluble Env trimers and that the glycan shield of well-formed HIV Env trimers is virtually impenetrable for murine B cell receptors (BCRs). IMPORTANCEHuman HIV vaccine efficacy trials have not generated meaningful neutralizing antibodies to circulating HIV strains. One possible hindrance has been the lack of immunogens that properly mimic the native conformation of the HIV envelope trimer protein. Here, we tested the first generation of soluble, native-like envelope trimer immunogens in a conventional mouse model. We attempted to generate neutralizing antibodies to neutralization-resistant circulating HIV strains. Various vaccine strategies failed to induce neutralizing antibodies to a neutralization-resistant HIV strain. Further analysis revealed that mouse antibodies targeted areas near the bottom of the soluble envelope trimers. These areas are not easily accessible on the HIV virion due to occlusion by the viral membrane and may have resulted from an absence of glycan shielding. Our results suggest that obscuring the bottom of soluble envelope trimers is a useful strategy to reduce antibody responses to epitopes that are not useful for virus neutralization.

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Section: Discussionmentioning

confidence: 97%

Murine Antibody Responses to Cleaved Soluble HIV-1 Envelope Trimers Are Highly Restricted in Specificity

Crampton

Cupo

et al. 2015

J Virol

156

179

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“…B cells then migrate into the dark zones where they proliferate and undergo somatic hypermutation, resulting in antibody diversification (reviewed in 106). The number of divisions B cells undergo in the dark zone and the speed of cycling are determined by the help provided by Tfh cells 107, 108. B cells then exit into the light zones, where those cells expressing surface Ig of sufficiently high affinity to enable them to efficiently acquire antigen from FDCs undergo further interactions with Tfh cells and receive signals, in particular via CD40, that enable continued survival.…”

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 speed of replication forks was implicated as a regulatory target in the DNA damage response (70-73) but not in developmental decisions in normal physiology. A recent report of faster forks in germinal center B cells receiving T cell help (74), together with our findings here in erythroid progenitors, raise the possibility that regulatory changes in global fork speed may be an intrinsic part of mammalian physiological developmental programs.…”

Section: Discussionmentioning

confidence: 72%

Global increase in replication fork speed during a p57KIP2-regulated erythroid cell fate switch

Socolovsky

Futran

Hidalgo

2017

Experimental Hematology

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Cell cycle regulators are increasingly implicated in cell fate decisions, such as the acquisition or loss of pluripotency and self-renewal potential. The cell cycle mechanisms that regulate these cell fate decisions are largely unknown. We studied an S phase-dependent cell fate switch, in which murine early erythroid progenitors transition in vivo from a self-renewal state into a phase of active erythroid gene transcription and concurrent maturational cell divisions. We found that progenitors are dependent on p57 KIP2 -mediated slowing of replication forks for self-renewal, a novel function for cyclin-dependent kinase inhibitors. The switch to differentiation entails rapid down-regulation of p57 KIP2 with a consequent global increase in replication fork speed and an abruptly shorter S phase. Our work suggests that cell cycles with specialized global DNA replication dynamics are integral to the maintenance of specific cell states and to cell fate decisions.

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T cell help controls the speed of the cell cycle in germinal center B cells

Cited by 206 publications

References 41 publications

Murine Antibody Responses to Cleaved Soluble HIV-1 Envelope Trimers Are Highly Restricted in Specificity

Murine Antibody Responses to Cleaved Soluble HIV-1 Envelope Trimers Are Highly Restricted in Specificity

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

Global increase in replication fork speed during a p57KIP2-regulated erythroid cell fate switch

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