University of Cambridge
Mechanisms Underpinning Functional Resident Humoral Lung Immunity
Abstract
dc:description.abstractTertiary lymphoid organs form de novo in response to allergy or infection, in the inflamed sites of autoimmune diseases and even adjacent to solid cancers. Whether or not these structures are functionally competent and can support antibody affinity maturation is unknown. This project aims to elucidate key differences between classic and ectopic germinal centres which may inform how we can improve medical interventions to enhance humoral protection against autoimmunity and infectious disease. B cells undergo selection in secondary lymphoid tissue germinal centres which can improve the way their B cell receptors bind antigen and generate antibodies that provide protection against infections. Due to their de novo formation and less stringent assembly, it is unknown whether tertiary lymphoid organs are functionally competent and can support antibody affinity maturation. Evolutionarily, an identical GC reaction in secondary and tertiary lymphoid organs may represent an energetically expensive duplication of efforts, and therefore I hypothesise that the spontaneously formed tertiary lymphoid organs fail to support efficient somatic hypermutation, thereby producing more broadly reactive antibodies. CD69 is an early-activation marker which is understood to be upregulated rapidly upon lymphocyte activation and can promote tissue-retention of T cells. I hypothesise that CD69 has a role in ectopic germinal centre function and tissue-resident memory B cell retention. The function and mechanism of CD69 for germinal centre B cells has yet to be elucidated, as well as its role in the formation and maintenance of ectopic germinal centres as distinct from those in secondary lymphoid organs. Here, I reveal fundamental differences and similarities in the humoral biology that underpins germinal centres in the lung and lymph nodes. Lung ectopic germinal centres were capable of supporting affinity maturation and seeding memory B cells, despite their de novo formation. While CD69 on T follicular helper cells was dispensable to maintain functional lymph node germinal centres, CD69 expression on B cells was important for their participation in both the lung and lymph node germinal centre reactions, suggesting a role for CD69 on B cells. This research contributes to current understandings of ectopic and conventional germinal centre biology and may have implications in improving vaccine design and medical interventions.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2024
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Guillaume, Stephane
- Advisor dc:contributor.advisor
-
- Linterman, Michelle
Subjects
dc:subject × 9Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.113799
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/376651