Investigating costimulatory molecule provision and regulation for CD4 T cell responses in vivo

Gajdasik, Dominika Weronika (2020). Investigating costimulatory molecule provision and regulation for CD4 T cell responses in vivo. University of Birmingham. Ph.D.

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Abstract

Interactions between the innate and adaptive immune systems have pivotal roles in the generation of effector and memory lymphocyte responses. This thesis focuses on the costimulatory pathways that regulate CD4 T cells development, specifically OX40:OX40L as the critical mechanism downstream of CD28 signalling. Whilst it is clear that CD4 T cell responses require signals through OX40 pathway, its role in T cell function as well as the cellular sources of its ligand in vivo and how its expression is regulated are poorly defined.

Here we reveal our studies across various in vivo immune response models, including attenuated Listeria and Salmonella models and the clinically approved immunostimulant AS01 adjuvant. Collectively, these approaches all demonstrated that OX40 signals were particularly important for the generation of effector CD4 T cell populations. We have shown that in responses to Listeria, the number of effector CD4 T cells expressing IFN\gamma was highly OX40 dependent. In the context of acute bacterial infection, we discovered that OX40L is rapidly upregulated on DC within the first 24hrs post infection and this is controlled by the innate cell production of IFN\gamma and in particular, dependent on IL-12 signals affecting the IFN\gamma production by NK cells. Furthermore, using the novel OX40L conditional knockout mice we have successfully shown that CD11c+ DC were the critical cellular sources of OX40L during the primary response to Listeria and that OX40L expression by T cells, ILC3 and B cells was redundant. Using the AS01 model we have demonstrated that although important for optimal CD4 T cell responses, the rapid production of innate IFN\gamma induced by the AS01 was not required for neither the upregulation of OX40L on DC nor the B cell responses generated post immunisation, confirming multiple mechanisms for OX40L regulation in a context dependent manner. Collectively, these studies highlight the importance of OX40 pathway across various in vivo immune responses and reveal new data on regulation of OX40L expression and its cell specific provision.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):