Soskic, B; (2017) The role of CD28 costimulation in T cell differentiation and function. Doctoral thesis , UCL (University College London).

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Abstract

The activation of CD4+ T cells is dependent upon two signals provided by professional antigen presenting cells APCs. The first signal, which determines the specificity of response, is generated by TCR recognition of antigen displayed by MHC II. In addition, in response to inflammatory signals, APCs upregulate the costimulatory ligands CD80 and CD86, which then interact with the CD28 receptor expressed on T cells. It has been demonstrated that CD80 and CD86 are expressed by activated T cells, but the significance of this observation remains unknown. Here, I show that activated CD4+ T cells express either CD80, CD86 or both. Surprisingly, CD80+ T cells had the hallmarks of induced regulatory T cells, expressing Foxp3 and high levels of CTLA-4. In contrast, CD86 was preferentially expressed on IFN-γ producing cells, which proliferated more extensively and had characteristics of effector T cells. Furthermore, it was observed that CD80 expressed on Tregs acts as an intrinsic ligand for CTLA-4, thus modulating CTLA-4 biology and consequently affecting Treg proliferation. Together these data establish endogenous expression of CD80 and CD86 by human T cells and highlight differences in their expression patterns. The requirements of naïve and memory T cells for CD28 costimulation were also compared. Although the importance of CD28 signalling in the activation of naïve T cells is widely appreciated, the requirement of CD28 engagement for the activation of memory T cells continues to be an area of debate. Surprisingly, I observed that under settings of high TCR stimulation memory T cells were more dependent upon CD28 costimulation than naïve T cells. In contrast, naïve T cells were capable of mounting strong responses to cross-linked anti-CD3 but not cross-linked anti-CD28. Together, these data revealed differential TCR and CD28 requirements of naïve and memory T cells.

Type:	Thesis (Doctoral)
Title:	The role of CD28 costimulation in T cell differentiation and function
Event:	UCL (University College London)
Language:	English
Keywords:	T cells, Costimulation
UCL classification:	UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI:	https://discovery.ucl.ac.uk/id/eprint/1541129

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