Role of IL-27 and TCR Stimulation in Inhibitory Receptor Expression

The adaptive immune response is necessary for control of pathogen burden in a wide range of infections. However, in the absence of active regulatory mechanisms, this protective response can lead to immune pathology. The cytokine interleukin (IL)-27 is required for control of exaggerated immune responses during toxoplasmosis and other infections and autoimmune settings. Multiple regulatory pathways have been found to be controlled by IL-27. However, there are gaps in our knowledge of the mechanisms by which IL-27 limits T cell responses. The present work focuses on the ability of IL-27 to promote expression of inhibitory receptors on T cells. The studies presented here establish that TCR and cytokines have distinct and complementary roles in promoting inhibitory receptor expression. In vitro, IL-27, type I IFN, and IFN-g induced expression of PD-L1 and Sca-1 on naïve murine CD4+ and CD8+ T cells in the absence of TCR stimulation. TCR stimulation induced expression of multiple inhibitory receptors and IL- 27 combined synergistically with TCR stimulation to further upregulate Ly6C, LAG-3, CTLA-4, TIGIT and TIM-3. This IL-27-mediated inhibitory expression was STAT1- dependent. The response to TCR stimulation was graded and thus a stronger TCR stimulus resulted in greater inhibitory receptor expression. In vivo, during infection with Toxoplasma gondii, IL-27 was required for full expression of Ly6C, PD-L1, LAG-3, CTLA-4, and TIGIT by parasite-specific T cells in the lung, a local site of infection, but not in the spleen. STAT1 was also required for full expression of LAG-3, CTLA-4, and TIGIT at local sites of infection. Taken together, these studies suggest a model in which inhibitory receptor expression on T cells is a graded regulatory pathway that is upregulated by exposure to increasing levels of TCR stimulation and cytokines present at sites of inflammation