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Musarrat, Tajkia (2019) Modulation of IL-10 production by CD3/CD55 induced Type 1 regulatory (Tr1) T-cells. PhD thesis, University of Nottingham.

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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:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Spendlove, Ian
Keywords:	IL-10, Tr1 cells, CD55
Subjects:	QS-QZ Preclinical sciences (NLM Classification) > QW Microbiology. Immunology > QW501 Immunology
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID:	56736
Depositing User:	Musarrat, Tajkia
Date Deposited:	11 Nov 2019 11:19
Last Modified:	19 Jul 2021 04:30
URI:	https://eprints.nottingham.ac.uk/id/eprint/56736

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