T cell priming in murine mycobacterial infection and disease.
Mycobacterium tuberculosis (Mtb) continues to pose a major health risk across the globe. Attempts to control the spread of the disease have been hampered by the lack of a vaccine that can protect against pulmonary tuberculosis (TB). Due to the nature of Mtb as an intracellular obligate human pathogen, it has a very complex relationship with the human immune system. To overcome TB, we must gain a better understanding of the immune system, how it interacts with Mtb and how it can be manipulated to generate a more protective immune response. Due to the intracellular nature of Mtb, research is focused on driving a T cell response to activate macrophages and thereby reduce infection. It has been shown that early priming conditions alter the downstream T cell phenotype. We have found this is true in the context of Mtb and priming T cells with a suboptimal epitope impacts the phenotype of antigen-specific T cells during the progression of infection in the lung and is associated with the expression of immunity. We do not fully understand the nature of this change and its wider effects that provide a more protective phenotype, but it highlights the power of TCR:Antigen:MHC priming interactions as a tool for vaccination research. We also addressed the importance of the environment on T cell function in the infected lung. The TB lesion is a complex, inhibitory environment and we chose to reduce one known inhibitory agent, nitric oxide and found this altered the phenotype of lung resident T cells and allowed them to become more differentiated. This increased differentiation was associated with increased expression of the protective cytokine IFN-γ and reduced bacterial burden. These data support the opportunity for focused therapeutic interventions that allow the immune response to function optimally. Overall, our work demonstrates that the T cell response to Mtb can be manipulated both at initiation and expression of function.
Supervisor(s)Andrea Cooper; Manish Pareek
Date of award2022-09-28
Author affiliationDepartment of Respiratory Sciences
Awarding institutionUniversity of Leicester