The risks of targeting co-inhibitory pathways to modulate pathogen-directed T cell responses
Authors: Helge Frebel, Annette Oxenius
Journal: Trends in Immunology (2013)

The identification of T cell co-inhibition as a central mechanism in the regulation of adaptive immunity during infectious diseases provides new opportunities for immunotherapeutic interventions. However, the fact that T cell activity is frequently downregulated during pathogen-directed responses suggests a pivotal physiological role of co-inhibitory pathways during infectious disease. Reports of exacerbated immunopathology in conditions of impaired co-inhibition foster the view that downregulation of T cell activity is an essential negative feedback mechanism that protects from excessive pathogen-directed immunity. Thus, targeting co-inhibitory pathways can bear detrimental potential through the deregulation of physiological processes. Here, we summarize recent preclinical and clinical interventions that report immune-related adverse events after targeting co-inhibitory pathways. The identification of T cell co-inhibition as a central mechanism in the regulation of adaptive immunity during infectious diseases provides new opportunities for immunotherapeutic interventions. However, the fact that T cell activity is frequently downregulated during pathogen-directed responses suggests a pivotal physiological role of co-inhibitory pathways during infectious disease. Reports of exacerbated immunopathology in conditions of impaired co-inhibition foster the view that downregulation of T cell activity is an essential negative feedback mechanism that protects from excessive pathogen-directed immunity. Thus, targeting co-inhibitory pathways can bear detrimental potential through the deregulation of physiological processes. Here, we summarize recent preclinical and clinical interventions that report immune-related adverse events after targeting co-inhibitory pathways. Co-signaling is an essential component in T cell activation and differentiation [1Sharpe A.H. 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Several co-inhibitory receptors of the immunoglobulin superfamily such as programmed death (PD)-1 or cytotoxic T lymphocyte-associated antigen (CTLA)-4 were initially identified as crucial for the establishment and maintenance of peripheral tolerance due to their suppression of self-reactive adaptive immune responses [3Nishimura H. et al.Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor.Immunity. 1999; 11: 141-151Abstract Full Text Full Text PDF PubMed Scopus (2222) Google Scholar, 4Tivol E.A. et al.Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4.Immunity. 1995; 3: 541-547Abstract Full Text PDF PubMed Scopus (2535) Google Scholar]. Co-inhibitory receptors were also assigned increasing relevance in the regulation of immune responses against altered self and foreign antigen. In cancer, various tumors exhibit high expression levels of co-inhibitory ligands which correlate with poor prognosis [5Peggs K.S. et al.Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy.Immunol. Rev. 2008; 224: 141-165Crossref PubMed Scopus (192) Google Scholar, 6Norde W.J. et al.Co-inhibitory molecules in hematological malignancies: targets for therapeutic intervention.Blood. 2012; 120: 728-736Crossref PubMed Scopus (60) Google Scholar]. Tumor-infiltrating T cells express multiple co-inhibitory receptors that compromise tumor-specific T cell responses [7Leach D.R. et al.Enhancement of antitumor immunity by CTLA-4 blockade.Science (New York, NY). 1996; 271: 1734-1736Crossref Scopus (3042) Google Scholar, 8Baitsch L. et al.Exhaustion of tumor-specific CD8(+) T cells in metastases from melanoma patients.J. Clin. Invest. 2011; 121: 2350-2360Crossref PubMed Scopus (652) Google Scholar]. In infection, co-inhibitory pathways modulate T cell immunity against all major classes of pathogens, that is, viruses, bacteria, protozoa, fungi, and nematode parasites [9Barber D.L. et al.Restoring function in exhausted CD8 T cells during chronic viral infection.Nature. 2006; 439: 682-687Crossref PubMed Scopus (3239) Google Scholar, 10Lazar-Molnar E. et al.Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis.Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 13402-13407Crossref PubMed Scopus (258) Google Scholar, 11Bhadra R. et al.Control of Toxoplasma reactivation by rescue of dysfunctional CD8+ T-cell response via PD-1-PDL-1 blockade.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 9196-9201Crossref PubMed Scopus (130) Google Scholar, 12Lazar-Molnar E. et al.The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum.Proc. Natl. Acad. Sci. 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In view of accumulating studies that suggest a profound role of T cell co-inhibition in tumor establishment and pathogen persistence, the interference with co-inhibitory pathways represents a promising approach to enhance protective immunity. Therefore, the benefit of treatment with blocking antibodies that target co-inhibitory receptors or ligands has been investigated in numerous animal models and clinical studies [6Norde W.J. et al.Co-inhibitory molecules in hematological malignancies: targets for therapeutic intervention.Blood. 2012; 120: 728-736Crossref PubMed Scopus (60) Google Scholar, 17Odorizzi P.M. Wherry E.J. Inhibitory receptors on lymphocytes: insights from infections.J. Immunol. 2012; 188: 2957-2965Crossref PubMed Scopus (130) Google Scholar]. Despite the documented therapeutic potential of co-inhibitory pathway interference during various infectious diseases [17Odorizzi P.M. Wherry E.J. Inhibitory receptors on lymphocytes: insights from infections.J. Immunol. 2012; 188: 2957-2965Crossref PubMed Scopus (130) Google Scholar], distinct studies have reported adverse events or overall detrimental consequences when interfering with T cell co-inhibition (Table 1). In line with these reports, our own findings suggest a vital role of T cell co-inhibition in the protection from immune-mediated tissue damage during persistent virus infection [18Frebel H. et al.Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice.J. Exp. Med. 2012; 209: 2485-2499Crossref PubMed Scopus (156) Google Scholar]. Our results and those of others highlight the release of negative immunoregulation to bear considerable detrimental potential in the form of severe immunopathology.Table 1Adverse events reported for interfering with co-inhibitory pathways during infectious diseases.Interference with co-inhibitoryPathogenreceptorligandAdverse eventRefsVirusesLCMV (persistent)PD-1PD-L1Fatal vascular pathology9Barber D.L. et al.Restoring function in exhausted CD8 T cells during chronic viral infection.Nature. 2006; 439: 682-687Crossref PubMed Scopus (3239) Google Scholar, 18Frebel H. et al.Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice.J. Exp. Med. 2012; 209: 2485-2499Crossref PubMed Scopus (156) Google Scholar, 29Mueller S.N. et al.PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice.J. Clin. Invest. 2010; 120: 2508-2515Crossref PubMed Scopus (118) Google ScholarPD-L1Increased destruction of splenic stroma28Mueller S.N. et al.Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection.Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 15430-15435Crossref PubMed Scopus (187) Google ScholarPD-L1(+high-dose anti-4-1BB)Increased apoptosis of virus-specific CD8 T cells49Vezys V. et al.4-1BB signaling synergizes with programmed death ligand 1 blockade to augment CD8 T cell responses during chronic viral infection.J. Immunol. 2011; 187: 1634-1642Crossref PubMed Scopus (80) Google ScholarSIVCTLA-4(+vaccination)Abolished effect of prophylactic vaccination47Hirao L.A. et al.Immune modulation through 4-1BB enhances SIV vaccine protection in non-human primates against SIVmac251 challenge.PLoS ONE. 2011; 6: e24250Crossref PubMed Scopus (18) Google ScholarCTLA-4(+ART + IDO)Fatal pancreatitis50Vaccari M. et al.Fatal pancreatitis in simian immunodeficiency virus SIV(mac251)-infected macaques treated with 2′,3′-dideoxyinosine and stavudine following cytotoxic-T-lymphocyte-associated antigen 4 and indoleamine 2,3-dioxygenase blockade.J. Virol. 2012; 86: 108-113Crossref PubMed Scopus (27) Google ScholarHSV-1PD-L1Aggravated herpetic stromal keratitis31Jun H. et al.B7-H1 (CD274) inhibits the development of herpetic stromal keratitis (HSK).FEBS Lett. 2005; 579: 6259-6264Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 78Channappanavar R. et al.Blocking of PDL-1 interaction enhances primary and secondary CD8 T cell response to herpes simplex virus-1 infection.PLoS ONE. 2012; 7: e39757Crossref PubMed Scopus (39) Google Scholargal-9Aggravated ocular lesions79Sehrawat S. et al.Role of Tim-3/galectin-9 inhibitory interaction in viral-induced immunopathology: shifting the balance toward regulators.J. Immunol. 2009; 182: 3191-3201Crossref PubMed Scopus (92) Google ScholarAdenovirusPD-1Aggravated liver pathology26Iwai Y. et al.PD-1 inhibits antiviral immunity at the effector phase in the liver.J. Exp. Med. 2003; 198: 39-50Crossref PubMed Scopus (346) Google ScholarCoronavirus (gliatropic)PD-L1Aggravated axonal bystander damage27Phares T.W. et al.Enhanced antiviral T cell function in the absence of B7-H1 is insufficient to prevent persistence but exacerbates axonal bystander damage during viral encephalomyelitis.J. Immunol. 2010; 185: 5607-5618Crossref PubMed Scopus (39) Google ScholarTheiler's murine encephalomyelitis virusPD-L1Aggravated CNS inflammation and demyelination80Duncan D.S. Miller S.D. CNS expression of B7-H1 regulates pro-inflammatory cytokine production and alters severity of Theiler's virus-induced demyelinating disease.PLoS ONE. 2011; 6: e18548Crossref PubMed Scopus (29) Google ScholarMHV-3PD-1Increased mortality38Chen Y. et al.Programmed death (PD)-1-deficient mice are extremely sensitive to murine hepatitis virus strain-3 (MHV-3) infection.PLoS Pathog. 2011; 7: e1001347Crossref PubMed Scopus (35) Google ScholarCoxsackievirus B3TIM-3Aggravated acute myocarditis39Frisancho-Kiss S. et al.Cutting edge: T cell Ig mucin-3 reduces inflammatory heart disease by increasing CTLA-4 during innate immunity.J. Immunol. 2006; 176: 6411-6415Crossref PubMed Scopus (117) Google ScholarHepatitis C virusPD-L1(+CD137L)Partial inhibition of virus-specific CD8 T cells48Fisicaro P. et al.Combined blockade of programmed death-1 and activation of CD137 increase responses of human liver T cells against HBV, but not HCV.Gastroenterology. 2012; 143: 1576-1585Abstract Full Text Full Text PDF PubMed Scopus (104) Google ScholarInfluenza virusPD-L1Impaired virus-specific CD8 T cell response52Talay O. et al.B7-H1 (PD-L1) on T cells is required for T-cell-mediated conditioning of dendritic cell maturation.Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 2741-2746Crossref PubMed Scopus (65) Google ScholarBacteriaL. monocytogenesPD-L1Reduced expansion of antibacterial CD8 T cells19Rowe J.H. et al.Innate IFN-gamma is essential for programmed death ligand-1-mediated T cell stimulation following Listeria monocytogenes infection.J. Immunol. 2012; 189: 876-884Crossref PubMed Scopus (15) Google ScholarS. typhimuriumPD-L1Increased mortality21Lee S.J. et al.B7-H1 (programmed cell death ligand 1) is required for the development of multifunctional Th1 cells and immunity to primary, but not secondary, Salmonella infection.J. Immunol. 2010; 185: 2442-2449Crossref PubMed Scopus (17) Google ScholarM. tuberculosisPD-1Fatal lung pathology10Lazar-Molnar E. et al.Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis.Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 13402-13407Crossref PubMed Scopus (258) Google Scholar, 22Barber D.L. et al.CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition.J. Immunol. 2010; 186: 1598-1607Crossref PubMed Scopus (252) Google ScholarCitrobacter rodentiumHVEMCD160Increased mortality70Shui J.W. et al.HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria.Nature. 2012; 488: 222-225Crossref PubMed Scopus (107) Google ScholarStr. pneumoniaeHVEMIncreased mortality70Shui J.W. et al.HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria.Nature. 2012; 488: 222-225Crossref PubMed Scopus (107) Google ScholarChlamydia muridarumPD-L1(+anti-TIM-3)Aggravated upper genital tract pathology81Peng B. et al.Enhanced upper genital tract pathologies by blocking Tim-3 and PD-L1 signaling pathways in mice intravaginally infected with Chlamydia muridarum.BMC Infect. Dis. 2011; 11: 347Crossref PubMed Scopus (22) Google ScholarProtozoaP. yoelii (strain Py-lethal)CTLA-4Increased mortality24Lepenies B. et al.CTLA-4 blockade differentially influences the outcome of non-lethal and lethal Plasmodium yoelii infections.Microbes Infect. 2007; 9: 687-694Crossref PubMed Scopus (27) Google ScholarPlasmodium bergheiCTLA-4Increased fatal cerebral malaria32Jacobs T. et al.Murine malaria is exacerbated by CTLA-4 blockade.J. Immunol. 2002; 169: 2323-2329PubMed Google ScholarP. berghei (in BALB/c mice)CTLA-4Increased fatal cerebral malaria30Hafalla J.C. et al.The CTLA-4 and PD-1/PD-L1 inhibitory pathways independently regulate host resistance to Plasmodium-induced acute immune pathology.PLoS Pathog. 2012; 8: e1002504Crossref PubMed Scopus (101) Google ScholarPD-L1Increased fatal cerebral malaria30Hafalla J.C. et al.The CTLA-4 and PD-1/PD-L1 inhibitory pathways independently regulate host resistance to Plasmodium-induced acute immune pathology.PLoS Pathog. 2012; 8: e1002504Crossref PubMed Scopus (101) Google ScholarL. mexicanaPD-L2Aggravated cutaneous lesions41Liang S.C. et al.PD-L1 and PD-L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis.Eur. J. Immunol. 2006; 36: 58-64Crossref PubMed Scopus (66) Google ScholarL. donovaniHVEMLIGHTDecreased hepatic parasite control45Stanley A.C. et al.Critical roles for LIGHT and its receptors in generating T cell-mediated immunity during Leishmania donovani infection.PLoS Pathog. 2011; 7: e1002279Crossref PubMed Scopus (25) Google ScholarNematodesT. cruziPD-L2Increased parasitemia42Dulgerian L.R. et al.Programmed death ligand 2 regulates arginase induction and modifies Trypanosoma cruzi survival in macrophages during murine experimental infection.Immunology. 2011; 133: 29-40Crossref PubMed Scopus (32) Google Scholar Open table in a new tab Here, we discuss the potential risk factors and considerations for the therapeutic targeting of co-inhibitory pathways during infectious diseases. We suggest that therapeutic approaches should take into account the biology of the pathogen and the elicited disease, the biology of the targeted co-inhibitory pathway, as well as specific characteristics of the individual being treated (Figure 1). Despite promising preclinical results from studies using diverse types of pathogens, several aspects of pathogen biology might contraindicate interference with co-inhibitory pathways. For example, programmed death ligand (PD-L)1 blockade prior to Listeria monocytogenes infection negatively affects antibacterial CD8 T cell responses [19Rowe J.H. et al.Innate IFN-gamma is essential for programmed death ligand-1-mediated T cell stimulation following Listeria monocytogenes infection.J. Immunol. 2012; 189: 876-884Crossref PubMed Scopus (15) Google Scholar]. The suppression is suggested to result from increased nitric oxide (NO) production by macrophages after PD-L1 blockade [20Yamazaki T. et al.Blockade of B7-H1 on macrophages suppresses CD4+ T cell proliferation by augmenting IFN-gamma-induced nitric oxide production.J. Immunol. 2005; 175: 1586-1592PubMed Google Scholar]. As macrophage-derived NO is a hallmark of infections with intracellular bacteria, PD-L1 blockade might also compromise T cell responses against other intracellular bacteria. Accordingly, deficient PD-1–PD-L1 signaling precipitates increased mortality after infection with the intracellular bacterium Salmonella typhimurium or Mycobacterium tuberculosis [21Lee S.J. et al.B7-H1 (programmed cell death ligand 1) is required for the development of multifunctional Th1 cells and immunity to primary, but not secondary, Salmonella infection.J. Immunol. 2010; 185: 2442-2449Crossref PubMed Scopus (17) Google Scholar, 22Barber D.L. et al.CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition.J. Immunol. 2010; 186: 1598-1607Crossref PubMed Scopus (252) Google Scholar]. Increased mortality is attributed to impaired T helper (Th)1 development in the former but to immunopathology due to excessive Th1 responses in the latter infection model. Despite this divergent impact of impaired co-inhibition, the immune responses elicited by these intracellular bacteria shared the protective function conferred by PD-1–PD-L1 signaling. Viral infection renders host cells targets for T cell-mediated killing. Hence, viral tropism can be relevant when interfering with co-inhibitory pathways, because the blockade of T cell co-inhibition can enhance cellular cytotoxicity and might affect vital organ functions due to enhanced killing of infected yet indispensable cell types [18Frebel H. et al.Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice.J. Exp. Med. 2012; 209: 2485-2499Crossref PubMed Scopus (156) Google Scholar, 23Rodig N. et al.Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis.Eur. J. Immunol. 2003; 33: 3117-3126Crossref PubMed Scopus (403) Google Scholar]. Of note, this consideration is only relevant for infections with noncytopathic viruses that leave infected host cells viable. Furthermore, strain-dependent variations in pathogen virulence also seem to impact the benefit of targeting co-inhibitory pathways [24Lepenies B. et al.CTLA-4 blockade differentially influences the outcome of non-lethal and lethal Plasmodium yoelii infections.Microbes Infect. 2007; 9: 687-694Crossref PubMed Scopus (27) Google Scholar]. Although CTLA-4 blockade during infections with strain Py17NL of Plasmodium yoelii results in improved parasite clearance devoid of overt immunopathology, treating mice infected with the more virulent strain Py-lethal leads to exacerbated inflammation and increased mortality. In addition to pathogen biology, several infection-related parameters should be considered when interfering with co-inhibitory pathways. The progression of persistent lymphocytic choriomeningitis virus (LCMV) infection is decisive for the therapeutic impact of PD-L1 blockade: treatment during early infection elicits fatal immunopathology, whereas treatment during established persistent infection enhances antiviral T cell responses without the development of adverse events [9Barber D.L. et al.Restoring function in exhausted CD8 T cells during chronic viral infection.Nature. 2006; 439: 682-687Crossref PubMed Scopus (3239) Google Scholar, 18Frebel H. et al.Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice.J. Exp. Med. 2012; 209: 2485-2499Crossref PubMed Scopus (156) Google Scholar]. Moreover, CTLA-4 blockade is without effect if conducted from day 3 of P. yoelii (strain Py-lethal) infection, but starting treatment on day 0 post-infection significantly increases mortality [24Lepenies B. et al.CTLA-4 blockade differentially influences the outcome of non-lethal and lethal Plasmodium yoelii infections.Microbes Infect. 2007; 9: 687-694Crossref PubMed Scopus (27) Google Scholar]. Analogously, PD-L1 blockade from day 0 of L. monocytogenes infection compromises antibacterial T cell immunity, whereas a slight delay of treatment enhances antibacterial T cell function [19Rowe J.H. et al.Innate IFN-gamma is essential for programmed death ligand-1-mediated T cell stimulation following Listeria monocytogenes infection.J. Immunol. 2012; 189: 876-884Crossref PubMed Scopus (15) Google Scholar]. The above studies highlight disease progression as an important factor for co-inhibitory interference, because even minor changes in injection schedules render treatments ineffective or detrimental. The LCMV model system also suggests that the extent of pathogen dissemination is crucial for the success of co-inhibitory pathway blockade. Mice infected with a rapidly controlled and therefore locally defined low inoculum dose of LCMV docile remain asymptomatic after early PD-L1 blockade. By contrast, high-dose infected mice in which the virus disseminates systemically succumb to lethal immunopathology after early PD-L1 blockade [18Frebel H. et al.Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice.J. Exp. Med. 2012; 209: 2485-2499Crossref PubMed Scopus (156) Google Scholar]. Studies of M. tuberculosis infection also highlight the importance of evaluating co-stimulatory pathway interference in vivo, because enhanced effector functions observed in vitro with human T cells after PD-1 blockade translate into fatal immunopathology in M. tuberculosis-infected PD-1 deficient mice [22Barber D.L. et al.CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition.J. Immunol. 2010; 186: 1598-1607Crossref PubMed Scopus (252) Google Scholar, 25Jurado J.O. et al.Programmed death (PD)-1:PD-ligand 1/PD-ligand 2 pathway inhibits T cell effector functions during human tuberculosis.J. Immunol. 2008; 181: 116-125PubMed Google Scholar]. Taken together, pathogen-specific factors such as cell tropism and strain-specific virulence, as well as infection-related parameters such as disease progression and pathogen dissemination, can determine the therapeutic benefit of co-inhibitory pathway interference. Ligand and receptor expression patterns define the physiological role of co-inhibitory pathways during pathogen-directed immune responses. Specific cell types protect themselves or nearby cells from T cell effector functions by upregulating co-inhibitory ligands. PD-L1 expression on hepatic endothelial and Kupffer cells has been reported to inhibit locally T cell effector functions, which protect from aggravated liver pathology during adenovirus infection [26Iwai Y. et al.PD-1 inhibits antiviral immunity at the effector phase in the liver.J. Exp. Med. 2003; 198: 39-50Crossref PubMed Scopus (346) Google Scholar]. PD-L1 expression on oligodendroglia in the central nervous system (CNS) of demyelinating coronavirus-infected mice suppresses T cell effector functions and might offer protection from fatal axonal bystander damage [27Phares T.W. et al.Enhanced antiviral T cell function in the absence of B7-H1 is insufficient to prevent persistence but exacerbates axonal bystander damage during viral encephalomyelitis.J. Immunol. 2010; 185: 5607-5618Crossref PubMed Scopus (39) Google Scholar]. Moreover, PD-L1 upregulation on fibroblast reticular cells dampens the destruction of the splenic architecture during persistent LCMV infection [28Mueller S.N. et al.Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection.Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 15430-15435Crossref PubMed Scopus (187) Google Scholar]. In the same infection model, PD-L1-deficiency on cells of nonhematopoietic origin elicits fatal immunopathology 6–7 days after infection [29Mueller S.N. et al.PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice.J. Clin. Invest. 2010; 120: 2508-2515Crossref PubMed Scopus (118) Google Scholar]. Although ligand expression patterns define the type and localization of protected target cells, co-inhibitory receptor expression determines the cell types and effector functions subject to negative regulation. Hence, interrupting signaling through a specific receptor can manifest in enhanced effector functions in specific cell types, which might be considered for the design of therapeutic approaches. The immunopathological processes observed in the LCMV and coronavirus system have been attributed to excessive pathogen-directed CD8 T cell responses [18Frebel H. et al.Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice.J. Exp. Med. 2012; 209: 2485-2499Crossref PubMed Scopus (156) Google Scholar, 27Phares T.W. et al.Enhanced antiviral T cell function in the absence of B7-H1 is insufficient to prevent persistence but exacerbates axonal bystander damage during viral encephalomyelitis.J. Immunol. 2010; 185: 5607-5618Crossref PubMed Scopus (39) Google Scholar, 29Mueller S.N. et al.PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice.J. Clin. Invest. 2010; 120: 2508-2515Crossref PubMed Scopus (118) Google Scholar]. Likewise, increased mortality after PD-L1 or CTLA-4 blockade during virulent malaria infection results from increased interferon (IFN)-γ production by CD8 T cells [30Hafalla J.C. et al.The CTLA-4 and PD-1/PD-L1 inhibitory pathways independently regulate host resistance to Plasmodium-induced acute immune pathology.PLoS Pathog. 2012; 8: e1002504Crossref PubMed Scopus (101) Google Scholar]. During herpes simplex virus (HSV)-1 and M. tuberculosis infection, impaired PD-1–PD-L1 signaling leads to pathogenic proinflammatory cytokine secretion of CD4 T cells [22Barber D.L. et al.CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition.J. Immunol. 2010; 186: 1598-1607Crossref PubMed Scopus (252) Google Scholar, 31Jun H. et al.B7-H1 (CD274) inhibits the development of herpetic stromal keratitis (HSK).FEBS Lett. 2005; 579: 6259-6264Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. Also, CTLA-4 blockade increases CD4 T cell expansion associated with significantly enhanced mortality during experimental blood-stage malaria [32Jacobs T. et al.Murine malaria is exacerbated by CTLA-4 blockade.J. Immunol. 2002; 169: 2323-2329PubMed Google Scholar]. Although most of the above studies have focused on the capacity of T cells to degranulate and produce IFN-γ, elevated levels of the proinflammatory mediators tumor necrosis factor (TNF) and interleukin (IL)-6 are frequently observed systemically in treated mice [14Frebel H. et al.How chronic viral infections impact on antigen-specific T-cell responses.Eur. J. Immunol. 2011; 40: 654-663Crossref Scopus (81) Google Scholar, 22Barber D.L. et al.CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition.J. Immunol. 2010; 186: 1598-1607Crossref PubMed Scopus (252) Google Scholar, 27Phares T.W. et al.Enhanced antiviral T cell function in the absence of B7-H1 is insufficient to prevent persistence but exacerbates axonal bystander damage during viral encephalomyelitis.J. Immunol. 2010; 185: 5607-5618Crossref PubMed Scopus (39) Google Scholar, 30Hafalla J.C. et al.The CTLA-4 and PD-1/PD-L1 inhibitory pathways independently regulate host resistance to Plasmodium-induced acute immune pathology.PLoS Pathog. 2012; 8: e1002504Crossref PubMed Scopus (101) Google Scholar]. Conflicting results have been published on the role of co-inhibitory receptors in the development and function of follicular helper T (Tfh) cells. PD-1-deficiency compromises the capacity of Tfh cells to promote germinal center formation after immunization with nitrophenol-chicken gamma globulin (NP-CGG), and naïve PD-1 knockout mice exhibit reduced fecal IgA levels due to a skewed Tfh cell cytokine profile in the gut [33Good-Jacobson K.L. et al.PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells.Nat. Immunol. 2010; 11: 535-542Crossref PubMed Scopus (550) Google Scholar, 34Kawamoto S. et al.The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut.Science (New York NY). 2012; 336: 485-489Crossref Scopus (354) Google Scholar]. However, PD-L1-deficient mice mount enhanced Tfh cell and humoral responses during Schistosoma mansoni infection, and the simultaneous blockade of PD-L1 and lymphocyte-activation gene (LAG)-3 boosted pathogen-specific Tfh cell and IgG production during P. yoelii infection [35Hams E. e