Investigating the in vivo requirements for the generation and survival of CD4⁺ memory T cells

Marriott, Clare Louisa (2016). Investigating the in vivo requirements for the generation and survival of CD4⁺ memory T cells. University of Birmingham. Ph.D.

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Abstract

Much work has been done to elucidate the role of costimulatory molecules in CD4⁺ T cell responses. However the advent of major histocompatibility class II tetramers now allows endogenous polyclonal populations to be tracked from the naive pool through the primary response to the memory phase. I have utilised this method to dissect the role of OX40, ICOS and CD28 in the 2W1S:I-Aᵇ⁺ CD4⁺ T cell response. Additionally I have developed a model of local immunisation in photoconvertible Kaede transgenic mice, allowing the migration of antigen-specific memory cells to be tracked from a given site.
Following infection with Listeria monocytogenes expressing 2W1S peptide, OX40 ligation specifically expanded T effector (Teff) cells which resulted in a memory cell pool skewed towards T effector memory (Tem) cells, while T follicular helper (TFH) cell and germinal centre formation was abrogated. ICOS was required only for the formation of TFH cells in the primary response and the subsequent generation of both T central memory and Tem cells. However signals through OX40, ICOS and CD28 were dispensable for the persistence of memory cells once formed. Upon secondary challenge again OX40 and ICOS were specifically required for the proliferation of Teff and TFH cells respectively while CD28 had a more general role in the optimal expansion of all T cell subsets. Thus a complex set of temporally separated costimulatory molecule interactions are required for optimal CD4⁺ memory T cells responses in vivo. My results indicate that amongst this CD4⁺ memory T cell pool, a secondary lymphoid tissue resident population reside.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):