The effect of the Roquin mutation on immunity to mycobacterium tuberculosis infection

Abstract

Mycobacterium tuberculosis is a major cause of mortality and morbidity worldwide. IFN-gamma (IFN-γ) is essential for the control of M. tuberculosis infection and increased expression of the costimulatory molecule, Inducible T cell Costimulator (ICOS) on CD4+ T cells has been found to enhance mycobacteria-specific IFN-γ production in TB patients. ICOS is a marker of T cell activation and is also expressed by T follicular helper (TFH) cells, the role of which in immunity to M. tuberculosis is not well understood. Sanroque (SAN) mice carry a point mutation in the E3 ligase gene, roquin, and display increased ICOS expression on their CD4+ T cells, resulting in enhanced T cell activation and increased numbers of TFH cells. Further, SAN mice also progressively develop autoimmune disease. In this thesis, young SAN mice were utilised to examine whether their increased ICOS expression and higher numbers of TFH cells would improve control of M. tuberculosis infection. SAN mice displayed enhanced control of early M. tuberculosis infection, resulting in delayed bacterial dissemination from the lung. By 8 weeks post infection however, despite the enhanced T cell activation and increased mycobacteria-specific IFN-γ production, the SAN mice were unable to maintain the control of chronic M. tuberculosis infection, with significantly higher bacterial load in the lungs and dysregulated granuloma formation compared with wild type (WT) mice. The mechanisms leading to this increased susceptibility were then investigated. Further findings indicated that the expression of the roquin mutation itself in both T cells and myeloid cells, and potentially non-haematopoietic cells is the cause of increased susceptibility to M. tuberculosis infection and this is independent of the numbers of TFH cells seen in the SAN mice. The role of TFH cells in immunity to intracellular pathogens is not clear. M. tuberculosis infection increases the number of TFH cells in C57Bl/6 mice. To dissect the function of TFH cells in response to M. tuberculosis, we differentiated naïve M. tuberculosis-specific CD4+ T cells in vitro into TFH-like cells producing high IL-21 and low levels of IFN-γ. When these cells were transferred into RAG1-/- mice, which were then infected with M. tuberculosis, they upregulated IFN-γ production, like TH1 cells and controlled M. tuberculosis infection more effectively than the transferred TH0 cells. These data suggest that TFH-like cells retain a degree of plasticity and can modulate their response to infection depending upon the stimuli received. In summary, these data demonstrate that both roquin and TFH cells play important roles in protective immunity against M. tuberculosis infection.