A GPR174–CCL21 module imparts sexual dimorphism to humoral immunity

Zhao, Ruozhu; Chen, Xin; Ma, Wenxue; Zhang, Jinyu; Guo, Jie; Zhong, Xiaojing; Yao, Jiacheng; Sun, Jiahui; Rubinfien, Julian; Zhou, X. Y.; Wang, Jianbin; Qi, Hai

doi:10.1038/s41586-019-1873-0

Cited by 82 publications

(73 citation statements)

References 19 publications

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“…This motif is required for proper chemokine signaling, including CCR7 and CXCR4 signaling, because loss of the TSS motif reduces Gα subunit activation, ERK phosphorylation, and impedes actin polymerization. Although some of these changes could be caused by an alternative CCL21 receptor found on the X chromosome ( Zhao et al, 2020 ), we believe this is not the case, because we found no differences in gender or specificity to CCL21. Thus, it seems plausible that upregulation of PD-L1 and CCR7/CXCR4 increases the opportunity for membrane interactions during maturation of the DC.…”

Section: Discussionmentioning

confidence: 65%

PD-L1 Reverse Signaling in Dermal Dendritic Cells Promotes Dendritic Cell Migration Required for Skin Immunity

et al. 2020

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SUMMARY Although the function of the extracellular region of programmed death ligand 1 (PD-L1) through its interactions with PD-1 on T cells is well studied, little is understood regarding the intracellular domain of PD-L1. Here, we outline a major role for PD-L1 intracellular signaling in the control of dendritic cell (DC) migration from the skin to the draining lymph node (dLN). Using a mutant mouse model, we identify a TSS signaling motif within the intracellular domain of PD-L1. The TSS motif proves critical for chemokine-mediated DC migration to the dLN during inflammation. This loss of DC migration, in the PD-L1 TSS mutant, leads to a significant decline in T cell priming when DC trafficking is required for antigen delivery to the dLN. Finally, the TSS motif is required for chemokine receptor signaling downstream of the Gα subunit of the heterotrimeric G protein complex, ERK phosphorylation, and actin polymerization in DCs.

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Section: Discussionmentioning

confidence: 65%

PD-L1 Reverse Signaling in Dermal Dendritic Cells Promotes Dendritic Cell Migration Required for Skin Immunity

et al. 2020

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“…Nature’s biological systems already show evidence of sophisticated multi-step immunization mechanisms. For example, when faced by invading pathogens, antibodies are quickly produced, migrate to the precise locations, and quickly neutralize, inactivate, or destroy the pathogens 11 .…”

Section: Introductionmentioning

confidence: 99%

Immunizing lithium metal anodes against dendrite growth using protein molecules to achieve high energy batteries

et al. 2020

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The practical applications of lithium metal anodes in high-energy-density lithium metal batteries have been hindered by their formation and growth of lithium dendrites. Herein, we discover that certain protein could efficiently prevent and eliminate the growth of wispy lithium dendrites, leading to long cycle life and high Coulombic efficiency of lithium metal anodes. We contend that the protein molecules function as a “self-defense” agent, mitigating the formation of lithium embryos, thus mimicking natural, pathological immunization mechanisms. When added into the electrolyte, protein molecules are automatically adsorbed on the surface of lithium metal anodes, particularly on the tips of lithium buds, through spatial conformation and secondary structure transformation from α-helix to β-sheets. This effectively changes the electric field distribution around the tips of lithium buds and results in homogeneous plating and stripping of lithium metal anodes. Furthermore, we develop a slow sustained-release strategy to overcome the limited dispersibility of protein in the ether-based electrolyte and achieve a remarkably enhanced cycling performance of more than 2000 cycles for lithium metal batteries.

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“…In general, estrogen displays an immune enhancing activity whereas testosterone, the primary male sex hormone, has a suppressive effect on the immune system. Testosterone has recently been shown to enhance the association of GPR174, an X chromosomeencoded G-protein coupled receptor, with Gai in response to its ligand CCL21 and suppress B cell positioning toward the follicular center and germinal center formation (85). This may lead to a weaker antibody response in males.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Reverses HDAC Inhibitor-Mediated Repression of Aicda and Class-Switching in Antibody and Autoantibody Responses by Downregulation of miR-26a

Casali

Shen

et al. 2020

Front. Immunol.

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Estrogen contributes to females' strong antibody response to microbial vaccines and proneness to autoimmunity, particularly antibody-mediated systemic autoimmunity, in females. We have hypothesized that this is due to estrogen-mediated potentiation of class switch DNA recombination (CSR) and somatic hypermutation (SHM). As we have shown, estrogen boosts AID expression, which is critical for both CSR and SHM, through upregulation of HoxC4, which together with NF-κB critically mediates Aicda (AID gene) promoter activation. We contend here that additional regulation of Aicda expression by estrogen occurs through epigenetic mechanisms. As we have shown, histone deacetylase inhibitors (HDIs) short-chain fatty acid (SCFA) butyrate and propionate as well as the pharmacologic HDI valproic acid upregulate miRNAs that silence AID expression, thereby modulating specific antibody responses in C57BL/6 mice and autoantibody responses in lupus-prone MRL/Fas lpr/lpr mice. Here, using constitutive knockout Esr1 −/− mice and B cells as well as conditional knockout Aicda cre/cre Esr1 flox/flox mice and B cells, we showed that the HDI-mediated downregulation of Aicda expression as well as the maturation of antibody and autoantibody responses is reversed by estrogen and enhanced by deletion of ERα or E2 inhibition. Estrogen's reversion of HDI-mediated inhibition of Aicda and CSR in antibody and autoantibody responses occurred through downregulation of B cell miR-26a, which, as we showed, targets Aicda mRNA 3 ′ UTR. miR-26a was significantly upregulated by HDIs. Accordingly, enforced expression of miR-26a reduced Aicda expression and CSR, while miR-26a-sponges (competitive inhibitors of miR-26a) increased Aicda expression and CSR. Thus, our findings show that estrogen reverses the HDI-mediated downregulation of AID expression and CSR through selective modulation of miR-26a. They also provide mechanistic insights into the immunomodulatory activity of this hormone and a proof-of-principle for using combined ER inhibitor-HDI as a potential therapeutic approach.

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A GPR174–CCL21 module imparts sexual dimorphism to humoral immunity

Cited by 82 publications

References 19 publications

PD-L1 Reverse Signaling in Dermal Dendritic Cells Promotes Dendritic Cell Migration Required for Skin Immunity

PD-L1 Reverse Signaling in Dermal Dendritic Cells Promotes Dendritic Cell Migration Required for Skin Immunity

Immunizing lithium metal anodes against dendrite growth using protein molecules to achieve high energy batteries

Estrogen Reverses HDAC Inhibitor-Mediated Repression of Aicda and Class-Switching in Antibody and Autoantibody Responses by Downregulation of miR-26a

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