Modulation of IL-10 production by CD3/CD55 induced Type 1 regulatory (Tr1) T-cells
Publication Date
July 19, 2019
Creator
Abstract
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.
Item Type
ethesis
Thesis Type
PhD
Supervisors
Subjects (LC)
Associated Schools / Departments
School of Medicine
eprints ID
56736
UoN Repository URI
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4244960.Thesis Final.Tajkia Musarrat.2019-05-14.pdf
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Full-text
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Examined
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