Regulation of Effector CD8+ T Cells During Mycobacterium tuberculosis Infection

Approximately one-third of the world's population is currently infected with Mycobacterium tuberculosis (Mtb), the bacillus that causes tuberculosis. Globally, it is the second leading cause of death by a single infectious agent. An effective vaccine is needed to stop this ongoing pandemic, but efforts to design one are hampered by our limited understanding of host immunity to this pathogen. CD8+ T cells are elicited during tuberculosis and are required for optimum host resistance. They produce cytokines such as IFN-gamma and can directly lyse infected cells. During infection, the expansion and differentiation of effector CD8+ T cells is a dynamically regulated process that is influenced by the inflammatory milieu of the infected host. Currently, the signals governing CD8+ T cell responses during tuberculosis are not well characterized. Utilizing a mouse model of disease, we address the effects of key cytokines on CD8+ T cells, beginning with IL-12, type 1 interferons (IFN), and IL-27. All three of these cytokines are produced by innate immune cells during tuberculosis and have profound effects on host resistance. IL-12 proves most essential for robust CD8+ T cell expansion and IFN-gamma production and also drives the terminal differentiation of short-lived effector cells. However, IL-12 is not acting alone, and type 1 IFN and IL-27 each have non-redundant roles supporting expansion in infected lungs. Thus, CD8 + T cells reflect the inflammatory environment of the host, responding in different degrees to each cytokine present. We next examine the role of IL-21, a cytokine produced by activated CD4+ T cells. In the absence of IL-21 signaling, CD8+ T cell expansion and effector functions are severely compromised. IL-21 is also essential to prevent CD8+ T cell exhaustion at later time points during disease. These observations are the first to describe an essential role for IL-21 in the host immune response to Mtb. Together, these studies establish IL-12 and IL-21 as essential regulators of CD8+ T cells during tuberculosis, and indicate type 1 IFN and IL-27 support expansion in the lungs. We believe these observations have implications for future immunotherapies and rational vaccine design.