Bar, one standard deviation

Bar, one standard deviation. Lm-induced IFN- production drives PDL-1-mediated T cell expansion Since direct T cell stimulation by IL-12 and type I IFNs are jointly non-essential for PDL-1-mediated expansion of Lm-specific T ML 161 cells, we investigated the role other cytokines such as IFN- known to be stimulated by IL-12 and type I IFNs have in controlling the T cell stimulatory impacts of PDL-1 (48C50). using mice with targeted defects in specific cytokines or cytokine receptors. These experiments illustrate an essential role for IL-12 or type I IFNs in PDL-1-mediated expansion of pathogen-specific CD8+ T cells. Unexpectedly, direct stimulation by neither IL-12 nor type I IFNs on pathogen-specific CD8+ cells was essential for PDL-1-mediated expansion. Instead, the absence of early innate IFN- production in mice with combined defects in both IL-12 and type I IFN receptor negated the impacts of PDL-1 blockade. Mouse monoclonal to CD22.K22 reacts with CD22, a 140 kDa B-cell specific molecule, expressed in the cytoplasm of all B lymphocytes and on the cell surface of only mature B cells. CD22 antigen is present in the most B-cell leukemias and lymphomas but not T-cell leukemias. In contrast with CD10, CD19 and CD20 antigen, CD22 antigen is still present on lymphoplasmacytoid cells but is dininished on the fully mature plasma cells. CD22 is an adhesion molecule and plays a role in B cell activation as a signaling molecule In turn, IFN- ablation using neutralizing antibodies or in mice with targeted defects in IFN- receptor each eliminated the PDL-1-mediated stimulatory impacts on pathogen-specific T cell expansion. Thus, innate IFN- is essential for PDL-1-mediated T cell stimulation. INTRODUCTION Programmed death ligand-1 (PDL-1, B7-H1) belongs to a growing list of co-stimulation molecules within the B7 family that regulate T cell activation (1C4). Best characterized after infection with Lymphocytic choriomeningitis virus (LCMV) and other viral pathogens that cause persistent infection, stimulation via PDL-1 sustains functional exhaustion for otherwise protective viral-specific CD8+ T cells (5). In turn, PDL-1 blockade using monoclonal antibodies during persistent infection or with therapeutic vaccination reinvigorates the activation of LCMV-specific CD8+ T cells and accelerates pathogen eradication (6). Similarly during hepatitis B or herpes simplex virus infection, PDL-1 neutralization stimulates the activation and IFN- production by virus-specific T cells (7, 8). These PDL-1-mediated immune suppressive properties initially described in mouse infection models extend to functional T cell exhaustion for humans infected with viruses that predominantly cause persistent infection. For example, CD8+ T cells with specificity to hepatitis C or human immune-deficiency virus each up-regulate the PDL-1 binding partner, PD-1, with progressively worsening infection (9C12). Reciprocally, PDL-1 blockade directly reverses the functional exhaustion, and stimulates proliferation and cytokine production by virus-specific human CD8+ T cells. Furthermore, for rabies virus that primarily cause acute instead of persistent infection, targeted defects in PDL-1 also protects against lethal infection (13). Taken together, these findings indicate PDL-1 compromises host defense against viral pathogens, and PDL-1 blockade may represent a promising strategy for boosting immunity against these infections. Interestingly and in striking contrast to immune suppression that ML 161 occurs during infection with viruses, the interaction between PDL-1 and PD-1 can also stimulate T cell activation and expansion that augments host defense against non-viral pathogens. For example, PDL-1 blockade impairs resistance and impedes the priming of protective CD8+ T cells after infection with the intracellular bacterium (Lm) (14, 15). In particular, expansion defects for Lm-specific T cells with PDL-1 blockade were apparent throughout primary infection and were associated with delayed re-expansion after secondary infection (15). Similarly, mice with defects in either PDL-1 or PD-1 have blunted expansion and activation of protective CD4+ T cells, and are more susceptible to other intracellular pathogens such as or (16C18). A stimulatory role for ML 161 PDL-1/PD-1 is further supported by the observation that most PD-1hi CD8+ T cells in healthy humans have an effector memory rather than exhausted phenotype (19). These findings illustrate that depending on the type of ML 161 infection, the interaction between PDL-1 and PD-1 can provide either immune activation or suppression signals that each play important roles in controlling infection susceptibility. Therefore, establishing the specific infection-induced signals that dictate whether PDL-1 stimulates immune activation or suppression is important as immune modulation therapies based on manipulating PDL-1 are being developed. In this study, we investigate how inflammatory cytokines induced by bacterial infection control PDL-1-mediated T cell stimulation. Given the interplay between the cytokines IL-12 and type I IFNs that each control PDL-1/PD-1 expression after infection with viral pathogens (13, 20C23), together with the efficiency whereby the intracellular bacterial pathogen Lm induces the production of these cytokines after infection (24C26), we initially focused on the role of IL-12 and type I IFNs in PDL-1-mediated stimulation of pathogen-specific T cells. Using mice with targeted individual or combined defects in these specific cytokines or their respective receptors, an essential role for either IL-12 or type I IFNs in PDL-1-mediated expansion of Lm-specific T cells is revealed. Unexpectedly however, the requirement for IL-12 and type I IFNs did not require direct stimulation by these cytokines on pathogen-specific T cells, but were instead indirectly mediated by the absence of early IFN- production after Lm infection in mice with combined defects in both IL-12 and type I IFN receptor. Together, these results uncover an essential role for innate IFN- in PDL-1-mediated T cell stimulation. MATERIALS AND METHODS Mice C57BL/6 (B6).