The role of interferon-gamma-mediated T cell collectivity on CD8+ T cell responses

Thesis

Immune responses towards intracellular pathogens and tumours rely on CD8+ T lymphocytes, whose function it is to kill infected or cancer cells, while sparing healthy tissue. CD8+ T cell immune responses are characterized by a remarkable degree of poly-clonality and poly-functionality. However, their overall population response is consistent and robust. Much research has focused on individual T cell activation, but how individual, heterogenous T cell responses are integrated at the population-level remains incompletely understood. Upon encountering their cognate antigen in secondary lymphoid organs, CD8+ T cells arrest for prolonged period of times around antigen-presenting cells forming dense cell clusters, which can function as communication hubs enabling T cells to directly communicate with each other and therefore directly modulate each other’s behaviour.

Here we investigated how CD8+ T cells regulate their response through direct T cell-T cell (T-T) communication, with a particular focus on the cytokine interferon-gamma (IFN-γ) and its effect on T cell responses. We found that specific deletion of the IFN-γ receptor on CD8+ T cells results in augmented expansion of antigen-specific effector T cells and in a skewing of the average functional avidity of the T cell repertoire, thus modulating multiple aspects of the response. In addition, we discovered that activating CD8+ T cells preferentially receive IFN-γ from other CD8+ T cells and furthermore that this IFN-γ-mediated communication between T cells is restricted to a specific time window during the activation phase of the response. Finally, we identified a specific CD8+ T cell subpopulation, so-called virtual-memory T cells, to function as the primary source of this early wave of IFN-γ. Altogether, this study highlights an underappreciated facet of the regulatory role of IFN-γ and virtual memory T cells on CD8+ T cell responses against infection.

Authors: Uhl, LFK

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: T cell; interferon-gamma
• Subjects: Immunology