Activation of MAIT cells, and their role in Mycobacterium tuberculosis infection
<p>Mucosal associated invariant T (MAIT) cells are a population of innate-like lymphocytes, with an emerging role in tuberculosis (TB). They are characterised by the expression of high levels of CD161 and IL-18Rα, possession of a Vα7.2<sup>+</sup> T cell receptor (TCR), and restric...
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| Format: | Thesis |
| Language: | English |
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2016
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| _version_ | 1797104349203136512 |
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| author | Bilton, M |
| author2 | Klenerman, P |
| author_facet | Klenerman, P Bilton, M |
| author_sort | Bilton, M |
| collection | OXFORD |
| description | <p>Mucosal associated invariant T (MAIT) cells are a population of innate-like lymphocytes, with an emerging role in tuberculosis (TB). They are characterised by the expression of high levels of CD161 and IL-18Rα, possession of a Vα7.2<sup>+</sup> T cell receptor (TCR), and restriction by the MHC class I-related protein (MR1). MAIT cells can be activated by MR1 presenting microbe-derived riboflavin metabolites; or, by the cytokines IL-12 and IL-18 in a TCR-independent fashion. How human MAIT cells integrate these signals for their activation in response to <em>Mtb</em> is unclear. Lymphatic TB (LNTB) is a common extra-pulmonary manifestation of TB; however, little is known about the status of MAIT cells in LNTB — or in other granulomatous diseases, such as sarcoidosis.</p> <p>In this study, an <em>in vitro</em> approach was used to probe MAIT cell activation by <em>Mtb</em>, and the roles of IL-12/-18, the TCR, cell–cell contact and the immunological synapse (IS). Following TCR ligation, TNFα expression was rapid and transient, and was enhanced following sustained IL-12/-18 exposure. IFNγ expression occurred following sustained exposure to ng/ml concentrations of IL-12/-18; however, alongside TCR stimulation, pg/ml concentrations were sufficient. Using an artificial bilayer system, CD161 was excluded from the central regions of the MAIT cell IS, whilst the distribution of IL-18Rα remained unaffected. In response to <em>Mtb</em> and BCG, MR1 was necessary for rapid activation and TNFα expression, IL-12/-18 were necessary for robust and sustained IFNy expression, whilst an anti-<em>Mtb</em> effect was indicated in an intracellular infection model. Assessment of patients with TB or sarcoid lymphadenopathy revealed a depletion of MAIT cells in the blood in sarcoidosis, but not LNTB. In both groups, MAIT cells could be detected within a proportion of sampled lymph nodes.</p> <p>Overall, these findings indicate the importance of inflammatory cytokine signals in the induction of high-intensity and sustained MAIT cell effector function, including in response to <em>Mtb</em>. The observation of a numerical deficiency of MAIT cells in sarcoidosis requires further investigation.</p> |
| first_indexed | 2024-03-07T06:32:34Z |
| format | Thesis |
| id | oxford-uuid:f6838397-c300-4d00-bac6-60914bc5a69c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:32:34Z |
| publishDate | 2016 |
| record_format | dspace |
| spelling | oxford-uuid:f6838397-c300-4d00-bac6-60914bc5a69c2022-03-27T12:35:33ZActivation of MAIT cells, and their role in Mycobacterium tuberculosis infectionThesishttp://purl.org/coar/resource_type/c_db06uuid:f6838397-c300-4d00-bac6-60914bc5a69cMucosal associated invariant T (MAIT) cell activationCytokine (IL-12, IL-18) and TCR mediated stimulation of MAIT cellsMAIT cells in Tuberculosis (TB)EnglishORA Deposit2016Bilton, MKlenerman, PLalvani, A<p>Mucosal associated invariant T (MAIT) cells are a population of innate-like lymphocytes, with an emerging role in tuberculosis (TB). They are characterised by the expression of high levels of CD161 and IL-18Rα, possession of a Vα7.2<sup>+</sup> T cell receptor (TCR), and restriction by the MHC class I-related protein (MR1). MAIT cells can be activated by MR1 presenting microbe-derived riboflavin metabolites; or, by the cytokines IL-12 and IL-18 in a TCR-independent fashion. How human MAIT cells integrate these signals for their activation in response to <em>Mtb</em> is unclear. Lymphatic TB (LNTB) is a common extra-pulmonary manifestation of TB; however, little is known about the status of MAIT cells in LNTB — or in other granulomatous diseases, such as sarcoidosis.</p> <p>In this study, an <em>in vitro</em> approach was used to probe MAIT cell activation by <em>Mtb</em>, and the roles of IL-12/-18, the TCR, cell–cell contact and the immunological synapse (IS). Following TCR ligation, TNFα expression was rapid and transient, and was enhanced following sustained IL-12/-18 exposure. IFNγ expression occurred following sustained exposure to ng/ml concentrations of IL-12/-18; however, alongside TCR stimulation, pg/ml concentrations were sufficient. Using an artificial bilayer system, CD161 was excluded from the central regions of the MAIT cell IS, whilst the distribution of IL-18Rα remained unaffected. In response to <em>Mtb</em> and BCG, MR1 was necessary for rapid activation and TNFα expression, IL-12/-18 were necessary for robust and sustained IFNy expression, whilst an anti-<em>Mtb</em> effect was indicated in an intracellular infection model. Assessment of patients with TB or sarcoid lymphadenopathy revealed a depletion of MAIT cells in the blood in sarcoidosis, but not LNTB. In both groups, MAIT cells could be detected within a proportion of sampled lymph nodes.</p> <p>Overall, these findings indicate the importance of inflammatory cytokine signals in the induction of high-intensity and sustained MAIT cell effector function, including in response to <em>Mtb</em>. The observation of a numerical deficiency of MAIT cells in sarcoidosis requires further investigation.</p> |
| spellingShingle | Mucosal associated invariant T (MAIT) cell activation Cytokine (IL-12, IL-18) and TCR mediated stimulation of MAIT cells MAIT cells in Tuberculosis (TB) Bilton, M Activation of MAIT cells, and their role in Mycobacterium tuberculosis infection |
| title | Activation of MAIT cells, and their role in Mycobacterium tuberculosis infection |
| title_full | Activation of MAIT cells, and their role in Mycobacterium tuberculosis infection |
| title_fullStr | Activation of MAIT cells, and their role in Mycobacterium tuberculosis infection |
| title_full_unstemmed | Activation of MAIT cells, and their role in Mycobacterium tuberculosis infection |
| title_short | Activation of MAIT cells, and their role in Mycobacterium tuberculosis infection |
| title_sort | activation of mait cells and their role in mycobacterium tuberculosis infection |
| topic | Mucosal associated invariant T (MAIT) cell activation Cytokine (IL-12, IL-18) and TCR mediated stimulation of MAIT cells MAIT cells in Tuberculosis (TB) |
| work_keys_str_mv | AT biltonm activationofmaitcellsandtheirroleinmycobacteriumtuberculosisinfection |