Modulation of IL-10 production by CD3/CD55 induced Type 1 regulatory (Tr1) T-cells
A healthy immune system is maintained in a state of balance between pro-inflammatory and anti-inflammatory cells. The paradigm for T-cell activation requires CD80/86:CD28 engagement resulting in differentiation of CD4+ T-helper cells. However, alternative costimulatory molecules may favour the induc...
| Main Author: | |
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| Format: | Thesis (University of Nottingham only) |
| Language: | English |
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2019
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| Online Access: | https://eprints.nottingham.ac.uk/56736/ |
| _version_ | 1848799372758745088 |
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| author | Musarrat, Tajkia |
| author_facet | Musarrat, Tajkia |
| author_sort | Musarrat, Tajkia |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | A healthy immune system is maintained in a state of balance between pro-inflammatory and anti-inflammatory cells. The paradigm for T-cell activation requires CD80/86:CD28 engagement resulting in differentiation of CD4+ T-helper cells. However, alternative costimulatory molecules may favour the induction of alternate T cell phenotypes such as Type 1 Regulatory (Tr1) T-cells. One such receptor-ligand pair is CD55-CD97. We have previously demonstrated that co-stimulation by CD3/CD55 results in the differentiation of naive CD4+ T-cells into Tr1 phenotype, defined as IL-10+, IFN-- and IL-4-. IL-10 is the predominant immune-suppressive cytokine produced by adaptive immune system and it is required for immune resolution, promoting tolerance and controlling autoimmunity. Considering the importance of IL-10 production in auto-immune diseases, we aimed to study the CD3/CD55 mediated IL-10 production in Multiple sclerosis (MS) patients. In our pilot study, CD3/CD55 stimulation of naïve CD4+ T-cells resulted in significantly lower level IL-10 production as well as lower number of IL-10+ Tr1 cells in MS patients compared to heathy donors. We further investigated the effect of MS associated immune-modulators on the CD3/CD55 mediated IL-10 production. Vitamin-D3 and Dexamethasone preferentially enhanced IL-10 secretion and increased the number of Tr1 cells following CD3/CD55 stimulation whereas IFN- demonstrated similar effect with both CD55 and CD28 costimulation.
To validate the phenotype of these Tr1 cells, we characterised the CD3/CD55 induced Tr1 cells in terms of cell surface molecules and transcription factors. CD3/CD55 induced IL-10+IFN-- Tr1 cells were LAG-3High, TIM-3High, CTLA-4High and PD-1High. These cells also expressed T-bet and c-MAF but did not express FoxP3, GATA-3 and HELIOS. The presence of immune-modulators that are used in MS treatment did not alter the transcription factor profile of the Tr1 cells. Importantly, c-MAF was only induced in IL-10+ Tr1 cells in response to CD3/CD55 but not to CD3/CD28 stimulation. c-MAF expression was persistent upon restimulation with CD3/CD55 and it was not induced by non-specific stimulation with PMA/Ionomycin, indicating that c-MAF induction could be an integral part of signalling for CD3/CD55 mediated IL-10 production.
Thus, our study demonstrates for the first time that CD3/CD55 induced Tr1 cells are best defined as IL-10+IFN--LAG-3HighPD-1Highc-MAFHigh. These cells express c-MAF which is induced by CD55 costimulation. Furthermore, the presence of immune-modulators has a significant effect on the induction of Tr1 cells and may provide another mechanism to modulate Tr1 cells in MS patients. |
| first_indexed | 2025-11-14T20:34:37Z |
| format | Thesis (University of Nottingham only) |
| id | nottingham-56736 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T20:34:37Z |
| publishDate | 2019 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-567362025-02-28T14:31:30Z https://eprints.nottingham.ac.uk/56736/ Modulation of IL-10 production by CD3/CD55 induced Type 1 regulatory (Tr1) T-cells Musarrat, Tajkia A healthy immune system is maintained in a state of balance between pro-inflammatory and anti-inflammatory cells. The paradigm for T-cell activation requires CD80/86:CD28 engagement resulting in differentiation of CD4+ T-helper cells. However, alternative costimulatory molecules may favour the induction of alternate T cell phenotypes such as Type 1 Regulatory (Tr1) T-cells. One such receptor-ligand pair is CD55-CD97. We have previously demonstrated that co-stimulation by CD3/CD55 results in the differentiation of naive CD4+ T-cells into Tr1 phenotype, defined as IL-10+, IFN-- and IL-4-. IL-10 is the predominant immune-suppressive cytokine produced by adaptive immune system and it is required for immune resolution, promoting tolerance and controlling autoimmunity. Considering the importance of IL-10 production in auto-immune diseases, we aimed to study the CD3/CD55 mediated IL-10 production in Multiple sclerosis (MS) patients. In our pilot study, CD3/CD55 stimulation of naïve CD4+ T-cells resulted in significantly lower level IL-10 production as well as lower number of IL-10+ Tr1 cells in MS patients compared to heathy donors. We further investigated the effect of MS associated immune-modulators on the CD3/CD55 mediated IL-10 production. Vitamin-D3 and Dexamethasone preferentially enhanced IL-10 secretion and increased the number of Tr1 cells following CD3/CD55 stimulation whereas IFN- demonstrated similar effect with both CD55 and CD28 costimulation. To validate the phenotype of these Tr1 cells, we characterised the CD3/CD55 induced Tr1 cells in terms of cell surface molecules and transcription factors. CD3/CD55 induced IL-10+IFN-- Tr1 cells were LAG-3High, TIM-3High, CTLA-4High and PD-1High. These cells also expressed T-bet and c-MAF but did not express FoxP3, GATA-3 and HELIOS. The presence of immune-modulators that are used in MS treatment did not alter the transcription factor profile of the Tr1 cells. Importantly, c-MAF was only induced in IL-10+ Tr1 cells in response to CD3/CD55 but not to CD3/CD28 stimulation. c-MAF expression was persistent upon restimulation with CD3/CD55 and it was not induced by non-specific stimulation with PMA/Ionomycin, indicating that c-MAF induction could be an integral part of signalling for CD3/CD55 mediated IL-10 production. Thus, our study demonstrates for the first time that CD3/CD55 induced Tr1 cells are best defined as IL-10+IFN--LAG-3HighPD-1Highc-MAFHigh. These cells express c-MAF which is induced by CD55 costimulation. Furthermore, the presence of immune-modulators has a significant effect on the induction of Tr1 cells and may provide another mechanism to modulate Tr1 cells in MS patients. 2019-07-19 Thesis (University of Nottingham only) NonPeerReviewed application/pdf en arr https://eprints.nottingham.ac.uk/56736/1/4244960.Thesis%20Final.Tajkia%20Musarrat.2019-05-14.pdf Musarrat, Tajkia (2019) Modulation of IL-10 production by CD3/CD55 induced Type 1 regulatory (Tr1) T-cells. PhD thesis, University of Nottingham. IL-10 Tr1 cells CD55 |
| spellingShingle | IL-10 Tr1 cells CD55 Musarrat, Tajkia Modulation of IL-10 production by CD3/CD55 induced Type 1 regulatory (Tr1) T-cells |
| title | Modulation of IL-10 production by CD3/CD55 induced Type 1 regulatory (Tr1) T-cells |
| title_full | Modulation of IL-10 production by CD3/CD55 induced Type 1 regulatory (Tr1) T-cells |
| title_fullStr | Modulation of IL-10 production by CD3/CD55 induced Type 1 regulatory (Tr1) T-cells |
| title_full_unstemmed | Modulation of IL-10 production by CD3/CD55 induced Type 1 regulatory (Tr1) T-cells |
| title_short | Modulation of IL-10 production by CD3/CD55 induced Type 1 regulatory (Tr1) T-cells |
| title_sort | modulation of il-10 production by cd3/cd55 induced type 1 regulatory (tr1) t-cells |
| topic | IL-10 Tr1 cells CD55 |
| url | https://eprints.nottingham.ac.uk/56736/ |