An overview of immunology research at the Babraham Institute

The Babraham Institute does fundamental research into lifelong health and healthy ageing. Using its Immunology programme as an example, we find out what research they focus on and how they collaborate to achieve impactful discoveries.
An overview of immunology research at the Babraham Institute
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The Babraham Institute is based a few miles outside of Cambridge city, and is dedicated to research in the biological and medical sciences. It is 75 years since the Institute was formed in 1948 to study animal physiology. In 1993 the Institute was restructured to form the centrepiece of the Babraham Research Campus that now has over 60 biotech and industry tenants. The interactions between scientists in the Immunology Programme and the science campus are deep rooted and currently comprise numerous collaborations and co-funded projects, including PhD studentships with the campus companies and the Cambridge Biomedical campus.

The Immunology Programme, together with the Epigenetics and Signalling Programmes, form the core science programmes of the Institute.  We have extensive collaborations with the Schools of Biological Sciences and Medicine at the University of Cambridge. Our PhD students are registered for their degree at Cambridge, and group leaders and postdocs are often members of Cambridge colleges with tutoring roles.  Five current professors in the University of Cambridge are former members of Babraham’s Immunology Programme.

The current Immunology Programme consists of five research group leaders, funded by the Biotechnology and Biological Sciences Research Council (BBSRC), one of the science funding bodies comprising UK Research and Innovation. With additional staff funded by grants, the programme has over 35 active researchers with a shared goal to deliver research that advances the frontiers of biology and contributes to the BBSRCs mission to deliver “Bioscience for an Integrated Understanding of Health”. In practice, this means we conduct fundamental research to address mechanistic questions in cellular and molecular immunology seeking to understand the “Rules of Life”. This is pursued in the context of ageing and has application in the development of vaccines and immunotherapies. Extensive collaboration with colleagues in academic medical centres across the UK and further afield generates impact and makes Babraham an excellent training environment for those interested in how basic research findings are translated into benefit for all.

A tight team

This year, Michelle Linterman celebrates 10 years as a group leader at Babraham. Her group has consistently produced highly significant work on the biology of the germinal centre (GC) reaction and vaccination responses across the lifespan. This includes recent ground-breaking research in both mouse and human immune responses [1, 2] which sheds light on how aged bodies produce less effective immune responses, and work during the pandemic on how age influences the antibody response to COVID-19 vaccines [3, 4]. These findings underpin new funded collaborations, as well as an ERC Consolidator Grant awarded to Michelle, which is funded by a UKRI Frontier Research Grant.

Anne Corcoran’s group has had a long-standing interest in the epigenetic mechanisms underpinning V(D)J recombination of the immunoglobulin loci. She discovered antisense transcription at the Ig locus, which contributes to the chromatin opening required for V- DJ recombination [5]. She has revealed how IL-7 influences VH gene selection in developing B cells. In addition to promoting survival and proliferation, IL-7 regulates key transcription factors and antisense transcripts in the IgH locus [6].  She has recently shown that individual Ig loci form unique structures underpinning antibody diversity, and participate in a B lineage-specific inter-chromosomal gene network (Mielczarek-2023 in press).

Martin Turner’s group has worked for over twenty years on the ZFP36-family of RNA binding proteins (RNB). This research is still yielding surprises, and in 2022 his group reported new mechanisms by which these RBP limits the speed of differentiation and cytotoxicity of CD8 T cells [7]. A role for ZFP36 proteins in limiting glycolysis and glutaminolysis was also reported [8, 9], which suggests these pathways are regulated post-transcriptionally through mRNA decay and translational control. We have a long history of developing novel genetically modified mouse models to understand cell function and physiology. New mouse models have recently demonstrated that one of these RBPs is responsive to the antigen affinity of the T cell receptor and converts this information into a biological response. The RBP, by limiting negative feedback loops, acts to convert this information into the sensing of cytokines that regulate CD8 T cell proliferation and differentiation [10]. This progress has opened up new research areas that are being expanded through a funded collaboration with industry and the award of a Wellcome Discovery grant to Martin. This work involves collaboration with colleagues in the Epigenetics Programme to understand the regulation of open chromatin by RBPs. Collaboration with the Signalling Programme investigate how RBPs may be responsive to phosphorylation or other covalent modifications, signal-regulated alternative splicing of mRNA and studies to map protein-protein interactions in activated lymphocytes.

The Immunology Programme’s work on CD8 T cell biology is being further developed in exciting new directions by Arianne Richard who joined the programme in 2022 as a tenure track group leader funded by an MRC Career Development Award. Arianne will build upon her previous work on early T cell activation [11, 12] by applying a multidisciplinary approach to understand the formation and persistence of CD8 T cell responses. This work will use molecular analysis of single cells and physiological systems in a combination of mouse and human immunology studies, and will take advantage of collaboration with colleagues in Babraham’s Epigenetics Programme.

Claudia Ribeiro de Almeida joined the Immunology Programme in November 2018 and shortly after was awarded a Wellcome Sir Henry Dale Fellowship to build on her original work on the molecular basis of Immunoglobulin class switch recombination [13].  Her research portfolio has expanded to include work on several RNA helicases and DNA repair mechanisms in the germinal centre response. This work complements research being conducted by Martin and Michelle in collaboration with Jonathan Houseley in Epigenetics that is uncovering new insights into the coordination of DNA damage responses and replication in GC B cells.

Growing aims

The Immunology Programme is a cornerstone of the Babraham Institute’s mission to be a leader in research that identifies new strategies to promote health across the life-course. Building upon our past achievements and combining our diverse expertise, we are uniquely placed to deliver fundamental new insight into the molecular and cellular biology of immunity and how it changes upon ageing. We plan to expand the immunology programme at Babraham to be a hub that integrates the fast moving and exciting area of RNA biology with cutting-edge immunology.

References

  1. Hill DL, Whyte CE, Innocentin S, Lee JL, Dooley J, Wang J, James EA, Lee JC, Kwok WW, Zand MS, Liston A, Carr EJ, Linterman MA (2021) Impaired HA-specific T follicular helper cell and antibody responses to influenza vaccination are linked to inflammation in humans. eLife, 10:e70554. https://doi.org/10.7554/elife.70554
  2. Silva-Cayetano A, Fra-Bido S, Robert PA, Innocentin S, Burton AR, Watson EM, Lee JL, Webb LMC, Foster WS, McKenzie RCJ, Bignon A, Vanderleyden I, Alterauge D, Lemos JP, Carr EJ, Hill DL, Cinti I, Balabanian K, Baumjohann D, Espeli M, Meyer-Hermann M, Denton AE, Linterman MA (2023) Spatial dysregulation of T follicular helper cells impairs vaccine responses in aging. Nature Immunology, :1–14. https://doi.org/10.1038/s41590-023-01519-9
  3. Silva-Cayetano A, Foster WS, Innocentin S, Belij-Rammerstorfer S, Spencer AJ, Burton OT, Fra-Bidó S, Lee JL, Thakur N, Conceicao C, Wright D, Barrett J, Evans-Bailey N, Noble C, Bailey D, Liston A, Gilbert SC, Lambe T, Linterman MA (2021) A booster dose enhances immunogenicity of the COVID-19 vaccine candidate ChAdOx1 nCoV-19 in aged mice. Med, 2(3):243-262.e8. https://doi.org/10.1016/j.medj.2020.12.006
  4. Collier DA, et. al. (2021) Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2. Nature, 596(7872):417–422. https://doi.org/10.1038/s41586-021-03739-1
  5. Bolland DJ, Wood AL, Johnston CM, Bunting SF, Morgan G, Chakalova L, Fraser PJ, Corcoran AE (2004) Antisense intergenic transcription in V(D)J recombination. Nature Immunology, 5(6):630–637. https://doi.org/10.1038/ni1068
  6. Baizan-Edge A, Stubbs BA, Stubbington MJT, Bolland DJ, Tabbada K, Andrews S, Corcoran AE (2021) IL-7R signaling activates widespread VH and DH gene usage to drive antibody diversity in bone marrow B cells. Cell Reports, 36(2):109349. https://doi.org/10.1016/j.celrep.2021.109349
  7. Petkau G, Mitchell TJ, Chakraborty K, Bell SE, D´Angeli V, Matheson L, Turner DJ, Saveliev A, Gizlenci O, Salerno F, Katsikis PD, Turner M (2022) The timing of differentiation and potency of CD8 effector function is set by RNA binding proteins. Nature Communications, 13(1):2274. https://doi.org/10.1038/s41467-022-29979-x
  8. Matheson LS, Petkau G, Sáenz-Narciso B, D’Angeli V, McHugh J, Newman R, Munford H, West J, Chakraborty K, Roberts J, Łukasiak S, Díaz-Muñoz MD, Bell SE, Dimeloe S, Turner M (2022) Multiomics analysis couples mRNA turnover and translational control of glutamine metabolism to the differentiation of the activated CD4+ T cell. Scientific Reports, 12(1):19657. https://doi.org/10.1038/s41598-022-24132-6
  9. Cicchetto AC, Jacobson EC, Sunshine H, Wilde BR, Krall AS, Jarrett KE, Sedgeman L, Turner M, Plath K, Iruela-Arispe ML, Vallim TQ de A, Christofk HR (2023) ZFP36-mediated mRNA decay regulates metabolism. Cell Reports, 42(5):112411. https://doi.org/10.1016/j.celrep.2023.112411
  10. Petkau G, Mitchell TJ, Evans MJ, Matheson L, Salerno F, Turner M (2023) Zfp36l1 establishes the high affinity CD8 T cell response by directly linking TCR affinity to cytokine sensing. bioRxiv, :2023.05.11.539978. https://doi.org/10.1101/2023.05.11.539978
  11. Richard AC, Lun ATL, Lau WWY, Göttgens B, Marioni JC, Griffiths GM (2018) T cell cytolytic capacity is independent of initial stimulation strength. Nature immunology, 19(8):849 858. https://doi.org/10.1038/s41590-018-0160-9
  12. Ma CY, Marioni JC, Griffiths GM, Richard AC (2020) Stimulation strength controls the rate of initiation but not the molecular organization of TCR-induced signalling. eLife, 9:e53948. https://doi.org/10.7554/elife.53948
  13. Almeida CR de, Dhir S, Dhir A, Moghaddam AE, Sattentau Q, Meinhart A, Proudfoot NJ (2018) RNA Helicase DDX1 Converts RNA G-Quadruplex Structures into R-Loops to Promote IgH Class Switch Recombination. Molecular Cell, 70(4):650-662.e8. https://doi.org/10.1016/j.molcel.2018.04.001

Top image by the Babraham Institute

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