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Title: CD55 costimulation induces differentiation of human T regulatory type - 1 (Tr1) cells
Author: Sutavani, Ruhcha V.
ISNI:       0000 0004 6496 2962
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2015
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Unlike other helper T cells, the co-stimulatory ligands responsible for T regulatory type-1 (Trl) cells differentiation remain undefined. Understanding the molecular interactions driving peripheral Trl differentiation is important because Trls potently regulate immune responses, by IL-10 production. In this study we show that co-stimulation of human naïve CD4+ cells through the CD97-CD55 interaction drives Trl activation, expansion and function. T cell activation and expansion was equipotent with CD55 or CD28 co-stimulation, however CD55 co-stimulation resulted in two IL-10 secreting populations. The majority of the IL-10 was secreted by the minor, Trl population (IL-10high IFN-y- IL-4-, <5% cells) that express Trl markers CD49b, LAG-3 and CD226. This Tr 1 phenotype was not re-stimulated by CD28. But on CD55 re-stimulation, Trls proliferated and maintained their differentiated IL-10 high phenotype. The Trls significantly suppressed effector T cell function in an IL-10 dependent manner. The remaining (>95%) cells adopted a Thl- like IFN-y + phenotype. However, in contrast to CD28 derived This, CD55 derived This demonstrated increased plasticity with the ability to co-express IL-10 when re-stimulated through CD55 or CD28. These data identify CD55 as a novel co-stimulator of human Trls and support a role for alternative co-stimulatory pathways in determining the fate of the growing number of T helper populations. In this study we also show a defect in Trls in the autoimmune disease Multiple Sclerosis (MS). In response to CD55 costimulation, naïve CD4+ cells from a cohort of MS patients did not differentiate into Trl cells as normal, however the CD55 induced Thl response was unaffected. These patients showed persistent lack of an IL-10h1gh Trl population on primary and secondary CD55 costimulation. Also, MS patients mounted stronger IFN-y responses compared to healthy controls. These data demonstrate an altered immune balance in MS and highlight a defect in the Trl response as a contributing factor of this change. Overall, this study demonstrates that CD55 acts as a potent co-stimulator and activator of human naive CD4+ cells resulting in the differentiation of a discrete Trl population that inhibits T cell function in an IL-10 dependent manner and maintains the Trl phenotype upon re-stimulation, in healthy individuals. However, there is a defect in this normal Tr 1 response in the autoimmune condition Multiple Sclerosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available