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Developmental Biology - Boosting Immune Response

Boosting Older People's Immune Response to Vaccines

Vaccines work by generating antibodies that are able to block the ability of pathogens to infect us. With age, the magnitude and quality of our germinal centre reaction declines...


Immune cells called T follicular helper cells are essential to the germinal centre response. In this study, a research team used mice and humans to investigate why T follicular helper cell numbers decline with age, and if there is a way to boost them upon vaccination.

As we age, the function of our immune system declines, rendering us more susceptible to infections and less able to generate protective immunity after vaccination. By understanding the cellular and molecular mechanisms underpinning poorer response in older individuals, researchers at the Babraham Institute in Cambridge, United Kingdom, were able to repurpose an existing treatment for genital warts. They were able to demonstrate how the treatment acted as an effective method in overcoming the age-related effects on two of the many cell types making up our immune system.

Results of their research are published online in the journal eLife.

Mice and humans show similar age-dependent changes in their immune system so this finding offers hope for easily increasing the robustness of vaccination response in our older population. Although the Linterman lab observed the mouse immune systems' had improved response through application of the genital wart cream - do not try this at home as yet!
"The current coronavirus pandemic highlights that older members of our families and communities are more susceptible to the morbidity and mortality associated with infectious diseases. Therefore, it is imperative that we understand how the immune system in older people works, and explore how we might be able to boost their immune responses to vaccines to ensure vaccines work better in this vulnerable part of our society."

Michelle A. Linterman PhD, Group Leader, Laboratory of Lymphocyte Signalling and Development, Babraham Institute, United Kingdom; Epigenetics Programme, Babraham Institute, United Kingdom.

Vaccines generate antibodies which are able to block pathogens ability to infect us. Antibody secreting cells are produced in the germinal centre immune reaction hub that forms after infection or vaccination. With age, the magnitude and quality of germinal centre reaction hubs decline.

Immune cells called T follicular helper cells are essential to the germinal centre response. In this study the team used mice and human cells to investigate why T follicular helper cell numbers decline with age, and if there is a way to boost them upon vaccination.
"The germinal centre response is a highly collaborative process that requires multiple cell types to interact at the right place and the right time. Therefore, it made sense to us that defects in one or more of these cell types could explain the poor germinal centre response observed in older individuals after vaccination."

Michelle A. Linterman PhD.

Researchers found that older mice and humans form fewer T follicular helper cells after vaccination, which is linked to a poor germinal centre and antibody response. By developing our understanding of the cellular and molecular events occurring in the germinal centre after vaccination, the researchers identified T follicular helper cells in older mice and people received less stimulatory interactions from their immune system co-workers.
After using imiquimod cream (currently used to treat genital warts in humans) on the site of immunization in older mice:

• numbers of stimulatory cells increased

• formation of T follicular helper cells was restored

• age-dependent defects in dendritic immune cell types was rescued

Demonstrating age-related defects in T follicular helper cell formation are reversible, and can be overcome therapeutically.

The full picture and evaluation of whether this approach will work as an intervention in humans requires more research into why the germinal centre response changes with age, and what can be done to overcome this. If accomplished, it could be that clinical trials are established to incorporate this knowledge into new vaccine formulations for older people.

Abstract
Germinal centres (GCs) are T follicular helper cell (Tfh)-dependent structures that form in response to vaccination, producing long-lived antibody secreting plasma cells and memory B cells that protect against subsequent infection. With advancing age the GC and Tfh cell response declines, resulting in impaired humoral immunity. We sought to discover what underpins the poor Tfh cell response in ageing and whether it is possible to correct it. Here, we demonstrate that older people and aged mice have impaired Tfh cell differentiation upon vaccination. This deficit is preceded by poor activation of conventional dendritic cells type 2 (cDC2) due to reduced type 1 interferon signalling. Importantly, the Tfh and cDC2 cell response can be boosted in aged mice by treatment with a TLR7 agonist. This demonstrates that age-associated defects in the cDC2 and Tfh cell response are not irreversible and can be enhanced to improve vaccine responses in older individuals.

Authors
Marisa Stebegg, Alexandre Bignon, Danika Lea Hill, Alyssa Silva-Cayetano, Christel Krueger, Ine Vanderleyden, Silvia Innocentin, Louis Boon, Jiong Wang, Martin S Zand, James Dooley, Jonathan Clark, Adrian Liston, Edward Carr and Michelle A Linterman.


Acknowledgements
The authors are grateful to Dr Wim Pierson for preparing E?-GFP and his technical support, Dr Alice Denton for the mouse artwork in Figure 7, Dr Helder Nakaya for the phenotypic data that accompanied the human microarray dataset, Dr Anne O’Garra for the TCR7 TCR-Tg mice, Dr Oliver Bannard for provision of the XL-1 blue E. coli carrying a pTRCHis-E?-GFP vector and Drs Geoff Butcher and Martin Turner for critical reading of the manuscript. We acknowledge the contribution of the Babraham Institute Biological Support Unit staff, who performed in vivo treatments of our animals and took care of animal husbandry. We thank the staff of the Babraham Flow Cytometry Facility for cell sorting and the Babraham Sequencing Facility for performing RNA sequencing. The authors are grateful to Dr Anne Corcoran for her input on the experiments with ageing animals. This study was supported by funding from the Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0407, BBS/E/B/000C0427 and the Campus Capability Core Grant to the Babraham Institute), the European Research Council (637801 TWILIGHT), and the European Union’s Horizon 2020 research and innovation programme ‘ENLIGHT-TEN’ under the Marie Sk?odowska-Curie grant agreement No.: 675395. We gratefully acknowledge the participation of all NIHR BioResource Centre Cambridge volunteers, and thank the NIHR BioResource Centre Cambridge and staff for their contribution. We thank the National Institute for Health Research and NHS Blood and Transplant. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health & Social Care.

Funding None of the authors received specific funding for this work.

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Mar 30 2020   Fetal Timeline   Maternal Timeline   News 




A mouse lymph node from young mouse fourteen days after immunisation. B cell follicles are in
yellow (IgD). While proliferating germinal centre cells in Blue,(Ki67) are shown within
B cell follicles. T cells are shown in green. CREDIT Babraham Institute.


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