Edner, Natalie Mona; (2020) Follicular helper T cell differentiation in autoimmune diabetes: Role of the CD28 pathway. Doctoral thesis (Ph.D), UCL (University College London).

Abstract

The CD28/CTLA-4 axis provides a crucial checkpoint in the maintenance of peripheral tolerance and T cell activation. In this thesis, we have explored the relationship between CD28 costimulation, CD4 T cell differentiation and the autoimmune disease, type 1 diabetes (T1D). The effect of varying the strength of CD28 engagement has been tested using flow cytometry and we have used single cell RNA sequencing to phenotype wildtype, CD28 heterozygous or CD28 deficient T cells responding to immunisation in vivo. This revealed that the level of CD28 engagement could markedly influence qualitative aspects of the T cell response, including follicular helper T cell (Tfh) differentiation, while T cell activation and proliferation were relatively insensitive to CD28 signal strength. The effect of CD28 costimulation blockade on Tfh differentiation was investigated using abatacept, a soluble CTLA-4 molecule. We found that abatacept inhibited immunisation-induced Tfh differentiation but this effect was decreased the longer after immunisation CD28 costimulation blockade was initiated. In a mouse model of diabetes, Tfh specific for pancreatic islet antigen were decreased after treatment with abatacept, suggesting an ongoing requirement for costimulation in Tfh responses to autoantigen. Furthermore, abatacept treatment reduced circulating Tfhlike cells in individuals with new onset T1D. With the help of unbiased analysis methods, that bypassed the requirement for manual gating, we were able to confirm the abatacept-induced Tfh reduction and also identify further T cell populations that were sensitive to CD28 costimulation blockade. Remarkably, by using predictive modelling and data-driven analysis, patient baseline Tfh profiles could be identified that were linked to the clinical response following abatacept treatment, as assessed by C-peptide retention at the 2-year time point. The findings presented in this thesis provide further insights into how CD28 costimulation shapes T cell responses and will aid our understanding of how treatments targeting the CD28 pathway are modulating immune responses.

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