| Mycobacterium tuberculosis poses a major health threat, causing two million deaths annually accompanied by a rising frequency of multidrug-resistant strains. CD4 T cells are crucial for defence against tuberculosis, as without these cells infection rapidly becomes lethal. Furthermore, adoptively transferred tuberculosis-specific CD4 T cells can strongly reduce bacterial loads, indicating their therapeutic potential. However, this protective effect only starts a week after infection and is incapable of providing pathogen eradication. Understanding what aspects of the CD4 T cell response are important for bacterial control will greatly enhance vaccine design and treatment options. In this proposal, I will investigate two arms of the CD4 T cell response against tuberculosis. First, I will examine how CD4 T cell responses are initiated, by analyzing recruitment of inflammatory monocytes to the infected lung and measuring how monocyte-derived dendritic cells instruct the activation and differentiation of tuberculosis-specific CD4 T cells. Second, I will examine which effector functions of CD4 T cells are required for controlling bacterial growth and I will test whether protective capacity of CD4 T cells can be enhanced by blocking inhibitory receptors. Comprehending the activation and effector function of CD4 T cells in tuberculosis infection will open new avenues for disease control. |
