PD-1 signaling has also been shown to modulate the balance between antimicrobial immune defense and immune-mediated tissue damage. For example, PD-1-deficient mice develop more severe hepatocellular injury than their wild-type (WT) littermates in response to adenovirus infection [9] . In a herpes simplex virus (HSV) stromal keratitis mouse model, blockade of PD-1 signaling led to increased HSV-1-specific effector CD4 + T cell expansion, IFN-c production, and exacerbated keratitis [10] . A functionallysignificant high level of PD-1 expression has been found to be maintained by exhausted CD8 + T cells in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), in primates exposed to simian immunodeficiency virus (SIV), and in humans suffering from infection with human immunodeficiency virus (HIV), hepatitis B or C virus (HBV or HCV), or human Tlymphotropic virus (HTLV). However, blockade of the PD-1/PD-Ls pathway efficiently restored the virus-specific effector functions of the exhausted T cells, and lead to substantially reduced in viral load [11, 12, 13, 14, 15] . The PD-1 signal is also known to play a key role in the chronicity of infections with bacteria (Helicobacter pylori and Schistosoma mansoni) [16, 17] , pathogenic fungus (Histoplasma capsulatum) [18] , and parasitic worms (Taenia crassiceps) [19] . It appears that a number of pathogenic microorganisms exploit the PD-1 signal in order to evade host immune responses and to establish persistent infection.