Systemic fates of non-classically restricted, commensal specific T cells
<p>Inflammatory Bowel Diseases (IBD), encompassing both Crohn’s disease and ulcerative colitis, are characterized by destruction of the gut epithelial barrier, dysbiosis and aberrant immune reactivity to the microbiota. Although multiple studies have revealed CD8+ T cell signatures in the tiss...
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2023
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| _version_ | 1797113120099926016 |
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| author | Farley, TK |
| author2 | Powrie, F |
| author_facet | Powrie, F Farley, TK |
| author_sort | Farley, TK |
| collection | OXFORD |
| description | <p>Inflammatory Bowel Diseases (IBD), encompassing both Crohn’s disease and ulcerative colitis, are characterized by destruction of the gut epithelial barrier, dysbiosis and aberrant immune reactivity to the microbiota. Although multiple studies have revealed CD8+ T cell signatures in the tissues and circulating PBMC of patients with IBD, the role of CD8+ T cells in the initiation or perpetuation of disease has remained understudied.</p>
<p>Work investigating the contribution of immunity to the commensal microbiota in the skin identified a population of innate like CD8+ T cells restricted by the MHC-Ib molecule H2-M3, that play critical roles in wound healing and barrier repair. However, these commensal reactive CD8+ T cells have not yet been described in the gut. Thus, the aim of this DPhil project was to describe commensal specific, innate-like CD8+ T cells in this tissue. To achieve this, we leveraged established H2-M3 tetramer tools to track commensal specific CD8+ T cell responses during homeostasis and a model of colitis wherein colonization with the pathobiont <em>Helicobacter hepaticus</em> and treatment with αIL-10R antibody mimics genetic susceptibility and aberrant reactivity to the microbiota found in some patients with IBD.</p>
<p>Using a range of histological and flowcytometry measurements, we describe the architecture of the colon with and without H2-M3 restricted and MHC-Ia restricted CD8+ T cells in homeostasis and colitis, illustrating that MHC-Ib restricted CD8+ T cells can dominantly contribute to the CD8+ T cell response during inflammation. Further, we confirm the residence of H2-M3 restricted commensal reactive CD8+ T cells in the large intestine where they adopt a primarily Tc1 phenotype, differing from their Tc17 signature in the skin. During inflammation, we also report an upregulation of H2M3 gene expression in whole colon tissue and colon organoids as well as an expansion of commensal reactive CD8+ T cells secreting pro-inflammatory cytokines. We also observed expansion of commensal reactive CD8+ T cells to the colon during colitis after skin association, where they again exhibit a pro-inflammatory Tc1 phenotype. Finally, subsequent computational identification of predicted H2-M3 binding peptides produced by <em>Helicobacter hepaticus</em>, we developed novel tetramer tools which illustrate the high relative frequency of H2-M3 restricted CD8+ T cells in naïve animals.</p>
<p>Taken together, these findings lay the groundwork for further investigation into the impact of commensal reactive CD8+ T cells on the etiology or perpetuation of IBD. </p> |
| first_indexed | 2024-04-09T03:57:38Z |
| format | Thesis |
| id | oxford-uuid:3fac6afe-09f2-4cd1-9d13-9d4013972ddb |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-04-09T03:57:38Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | oxford-uuid:3fac6afe-09f2-4cd1-9d13-9d4013972ddb2024-04-02T12:04:25ZSystemic fates of non-classically restricted, commensal specific T cells Thesishttp://purl.org/coar/resource_type/c_db06uuid:3fac6afe-09f2-4cd1-9d13-9d4013972ddbMucosal ImmunologyColitisImmunologyMicrobiotaEnglishHyrax Deposit2023Farley, TKPowrie, F<p>Inflammatory Bowel Diseases (IBD), encompassing both Crohn’s disease and ulcerative colitis, are characterized by destruction of the gut epithelial barrier, dysbiosis and aberrant immune reactivity to the microbiota. Although multiple studies have revealed CD8+ T cell signatures in the tissues and circulating PBMC of patients with IBD, the role of CD8+ T cells in the initiation or perpetuation of disease has remained understudied.</p> <p>Work investigating the contribution of immunity to the commensal microbiota in the skin identified a population of innate like CD8+ T cells restricted by the MHC-Ib molecule H2-M3, that play critical roles in wound healing and barrier repair. However, these commensal reactive CD8+ T cells have not yet been described in the gut. Thus, the aim of this DPhil project was to describe commensal specific, innate-like CD8+ T cells in this tissue. To achieve this, we leveraged established H2-M3 tetramer tools to track commensal specific CD8+ T cell responses during homeostasis and a model of colitis wherein colonization with the pathobiont <em>Helicobacter hepaticus</em> and treatment with αIL-10R antibody mimics genetic susceptibility and aberrant reactivity to the microbiota found in some patients with IBD.</p> <p>Using a range of histological and flowcytometry measurements, we describe the architecture of the colon with and without H2-M3 restricted and MHC-Ia restricted CD8+ T cells in homeostasis and colitis, illustrating that MHC-Ib restricted CD8+ T cells can dominantly contribute to the CD8+ T cell response during inflammation. Further, we confirm the residence of H2-M3 restricted commensal reactive CD8+ T cells in the large intestine where they adopt a primarily Tc1 phenotype, differing from their Tc17 signature in the skin. During inflammation, we also report an upregulation of H2M3 gene expression in whole colon tissue and colon organoids as well as an expansion of commensal reactive CD8+ T cells secreting pro-inflammatory cytokines. We also observed expansion of commensal reactive CD8+ T cells to the colon during colitis after skin association, where they again exhibit a pro-inflammatory Tc1 phenotype. Finally, subsequent computational identification of predicted H2-M3 binding peptides produced by <em>Helicobacter hepaticus</em>, we developed novel tetramer tools which illustrate the high relative frequency of H2-M3 restricted CD8+ T cells in naïve animals.</p> <p>Taken together, these findings lay the groundwork for further investigation into the impact of commensal reactive CD8+ T cells on the etiology or perpetuation of IBD. </p> |
| spellingShingle | Mucosal Immunology Colitis Immunology Microbiota Farley, TK Systemic fates of non-classically restricted, commensal specific T cells |
| title | Systemic fates of non-classically restricted, commensal specific T cells |
| title_full | Systemic fates of non-classically restricted, commensal specific T cells |
| title_fullStr | Systemic fates of non-classically restricted, commensal specific T cells |
| title_full_unstemmed | Systemic fates of non-classically restricted, commensal specific T cells |
| title_short | Systemic fates of non-classically restricted, commensal specific T cells |
| title_sort | systemic fates of non classically restricted commensal specific t cells |
| topic | Mucosal Immunology Colitis Immunology Microbiota |
| work_keys_str_mv | AT farleytk systemicfatesofnonclassicallyrestrictedcommensalspecifictcells |