OX40 Stimulation Enhances Protective Immune Responses Induced After Vaccination With Attenuated Malaria Parasites (original) (raw)
Proceedings of the National Academy of Sciences, 2012
Previous reports have shown that γδ T cells are important for the elimination of malaria parasites in humans and mice. However, how γδ T cells are involved in protective immunity against bloodstage malaria remains unknown. We infected γδ T-cell-deficient (TCRδ-KO) mice and control wild-type mice with Plasmodium berghei XAT, which is a nonlethal strain. Although infected red blood cells were eliminated within 30 d after infection, TCRδ-KO mice could not clear the infected red blood cells, showed high parasitemia, and eventually died. Therefore, γδ T cells are essential for clearance of the parasites. Here, we found that γδ T cells play a key role in dendritic cell activation after Plasmodium infection. On day 5 postinfection, γδ T cells produced IFN-γ and expressed CD40 ligand during dendritic cell activation. These results suggest that γδ T cells enhance dendritic cell activation via IFN-γ and CD40 ligand-CD40 signaling. This hypothesis is supported strongly by the fact that in vivo induction of CD40 signaling prevented the death of TCRδ-KO mice after infection with P. berghei XAT. This study improves our understanding of protective immunity against malaria and provides insights into γδ T-cell-mediated protective immunity against various infectious diseases.
Impairment of Antigen-Presenting Cell Function in Mice Lacking Expression of Ox40 Ligand
Journal of Experimental Medicine, 2000
OX40 expressed on activated T cells is known to be an important costimulatory molecule on T cell activation in vitro. However, the in vivo functional significance of the interaction between OX40 and its ligand, OX40L, is still unclear. To investigate the role of OX40L during in vivo immune responses, we generated OX40L-deficient mice and a blocking anti-OX40L monoclonal antibody, MGP34. OX40L expression was demonstrated on splenic B cells after CD40 and anti-immunoglobulin (Ig)M stimulation, while only CD40 ligation was capable of inducing OX40L on dendritic cells. OX40L-deficient and MGP34-treated mice engendered apparent suppression of the recall reaction of T cells primed with both protein antigens and alloantigens and a significant reduction in keyhole limpet hemocyanin–specific IgG production. The impaired T cell priming was also accompanied by a concomitant reduction of both T helper type 1 (Th1) and Th2 cytokines. Furthermore, antigen-presenting cells (APCs) derived from the ...
Journal of immunology (Baltimore, Md. : 1950), 2003
Efficient T cell priming by GM-CSF and CD40 ligand double-transduced C26 murine colon carcinoma is not sufficient to cure metastases in a therapeutic setting. To determine whether a cellular vaccine that interacts directly with both APC and T cells in vivo might be superior, we generated C26 carcinoma cells transduced with the T cell costimulatory molecule OX40 ligand (OX40L) either alone (C26/OX40L) or together with GM-CSF (C26/GM/OX40L), which is known to activate APC. Mice injected with C26/OX40L cells displayed only a delay in tumor growth, while the C26/GM/OX40L tumor regressed in 85% of mice. Tumor rejection required granulocytes, CD4+, CD8+ T cells, and APC-mediated CD40-CD40 ligand cosignaling, but not IFN-gamma or IL-12 as shown using subset-depleted and knockout (KO) mice. CD40KO mice primed with C26/GM/OX40L cells failed to mount a CTL response, and T cells infiltrating the C26/GM/OX40L tumor were OX40 negative, suggesting an impairment in APC-T cell cross-talk in CD40KO ...
Proceedings of the National Academy of Sciences, 2005
Immunization with Plasmodium sporozoites that have been attenuated by ␥-irradiation or specific genetic modification can induce protective immunity against subsequent malaria infection. The mechanism of protection is only known for radiation-attenuated sporozoites, involving cell-mediated and humoral immune responses invoked by infected hepatocytes cells that contain longlived, partially developed parasites. Here we analyzed sporozoites of Plasmodium berghei that are deficient in P36p (p36p ؊ ), a member of the P48͞45 family of surface proteins. P36p plays no role in the ability of sporozoites to infect and traverse hepatocytes, but p36p ؊ sporozoites abort during development within the hepatocyte. Immunization with p36p ؊ sporozoites results in a protective immunity against subsequent challenge with infectious wild-type sporozoites, another example of a specifically genetically attenuated sporozoite (GAS) conferring protective immunity. Comparison of biological characteristics of p36p ؊ sporozoites with radiation-attenuated sporozoites demonstrates that liver cells infected with p36p ؊ sporozoites disappear rapidly as a result of apoptosis of host cells that may potentiate the immune response. Such knowledge of the biological characteristics of GAS and their evoked immune responses are essential for further investigation of the utility of an optimized GAS-based malaria vaccine.
Journal of Immune Based Therapies and Vaccines, 2011
Background: The induction of sterile immunity and long lasting protection against malaria has been effectively achieved by immunization with sporozoites attenuated by gamma-irradiation or through deletion of genes. For mice immunized with radiation attenuated sporozoites (RAS) it has been shown that intrahepatic effector memory CD8 + T cells are critical for protection. Recent studies have shown that immunization with genetically attenuated parasites (GAP) in mice is also conferred by liver effector memory CD8 + T cells. Findings: In this study we analysed effector memory cell responses after immunization of GAP that lack the P52 protein. We demonstrate that immunization with p52 -GAP sporozoites also results in a strong increase of effector memory CD8 + T cells, even 6 months after immunization, whereas no specific CD4 + effector T cells response could be detected. In addition, we show that the increase of effector memory CD8 + T cells is specific for the liver and not for the spleen or lymph nodes. Conclusions: These results indicate that immunization of mice with P. berghei p52 -GAP results in immune responses that are comparable to those induced by RAS or GAP lacking expression of UIS3 or UIS4, with an important role implicated for intrahepatic effector memory CD8 + T cells. The knowledge of the mediators of protective immunity after immunization with different GAP is important for the further development of vaccines consisting of genetically attenuated sporozoites.
Ox40Ligand Has a Critical Costimulatory Role in Dendritic Cell:T Cell Interactions
Immunity, 1999
also been implicated in T cell costimulation and/or antigen-presenting cell (APC) activation. Because of the Brigham and Women's Hospital and the Department of Pathology plethora of suggested costimulatory interactions, it is not clear which interactions are essential for generating Harvard Medical School Boston, Massachusetts 02115 an immune response and whether these pathways have unique or overlapping functions. 2 Department of Adult Oncology Dana Farber Cancer Institute Recent studies have pointed to a role for the Ox40:Ox40L pathway in CD4 ϩ T cell activation, differen-and the Department of Medicine Harvard Medical School tiation, and effector function, as well as in T cell homing, B cell activation, and dendritic cell function. Expression Boston, Massachusetts 02115 3 Immunex Research and Development of Ox40L, a TNF family member, has been reported on numerous activated immune system cell types, includ-Seattle, Washington 98101 4 Statistics were calculated using the parametric paired t test set to Cella, M., Sallusto, F., and Lanzavecchia, A. (1997). Origin, maturation and antigen presenting function of dendritic cells. Curr. Opin. 95% confidence interval and 2-sided p value. Immunol. 9, 10-16. For whole lymph node restimulation, mice were sensitized with DNFB. Draining lymph node cells (inguinal and axillary) were har-Cher, D.J., and Mosmann, T.R. (1987). Two types of murine helper vested 5 days after initial sensitization and pooled from like mice. T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 Cells at 1 ϫ 10 6 /ml were restimulated with DNBS in triplicate wells clones. J. Immunol. 138, 3688-3694. as in Figure 4. Cytokine data are from maximal time point of assay Colligan, J., Kruisbeck, A., Marguiles, D., Shevach, E., and Strober, and taken from proliferation wells. Proliferation and cytokines were W. (1994). Current Protocols in Immunology, R. Coico, ed. (NY: John analyzed as described (Schweitzer and Sharpe, 1998). Wiley and Sons). For CD4 ϩ , CD8 ϩ , and Thy1.2 ϩ T cell restimulation, mice were Flynn, S., Toellner, K.M., Raykundalia, C., Goodall, M., and Lane, sensitized with oxazolone. Draining lymph nodes (inguinal and axil-P. (1998). CD4 T cell cytokine differentiation: the B cell activation lary) were harvested on day 5 after initial sensitization, pooled from molecule, OX40 ligand, instructs CD4 T cells to express interleukin like mice, and T cell subsets were isolated by MACS. Irradiated, 4 and upregulates expression of the chemokine receptor, Blr-1. J. oxazolone-conjugated wild-type splenocytes (7.5 ϫ 10 4 ) were plated Exp. Med. 188, 297-304. with purified T cells in triplicate as in Figure 4. Oxazolone-conjugated Gimmi, C.D., Freeman, G.J., Gribben, J.G., Sugita, K., Freedman, splenocytes were prepared by incubating red blood cell depleted A.S., Morimoto, C., and Nadler, L.M. (1991). B-cell surface antigen splenocytes in 0.0375% oxazolone in 7.5% ethanol in PBS for 15 min B7 provides a costimulatory signal that induces T cells to proliferate at 23ЊC. Cells were irradiated, passed over Ficoll, and extensively and secrete interleukin 2. Proc. Natl. Acad. Sci. USA 88, 6575-6579. washed. Data shown are from the maximal time point. Gocinski, B.L., and Tigelaar, R.E. (1990). Roles of CD4ϩ and CD8ϩ T cells in murine contact sensitivity revealed by in vivo monoclonal Dendritic Cell-Induced MLR antibody depletion. J. Immunol. 144, 4121-4128. Dendritic cells from Flt3L-treated 129/Sv animals were isolated from Godfrey, W.R., Fagnoni, F.F., Harara, M.A., Buck, D., and Engleman, spleen by MACS. Dendritic cells (10 5 ) were irradiated and plated in E.G. (1994). Identification of a human OX-40 ligand, a costimulator triplicate with BALB/c CD4 ϩ T cells isolated by MACS as in Figure of CD4ϩ T cells with homology to tumor necrosis factor. J. Exp. 5. Proliferation and cytokine data are from time point of maximal Med. 180, 757-762. response for each assay. Grabbe, S., and Schwarz, T. (1998). Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity. Immunol. Acknowledgments Today 19, 37-44. for technical T. (1995). Removal of the majority of epidermal Langerhans cells by assistance and Rebecca Greenwald, Mariette Oosterwegel, Ifor Wiltopical or systemic steroid application enhances the effector phase liams, Jacques Peschon, and especially Bruce Blazar for helpful of murine contact hypersensitivity. J. Immunol. 155, 4207-4217. discussion. This work was supported by the National Institutes of Gramaglia, I., Weinberg, A.D., Lemon, M., and Croft, M. (1998). Ox-Health grants AI/GF41584 and AR42689 (to A. H. S.). A. I. C. is 40 ligand: a potent costimulatory molecule for sustaining primary supported in part by the Medical Scientist Training Program of Har-CD4 T cell responses.
The Journal of Immunology, 2021
Radiation-attenuated sporozoite (RAS) vaccination offers hope for global malaria control through induction of protective liver-stage–specific memory CD8 T cells. Effective RAS vaccination regimens exist; however, widespread implementation remains unfeasible. A key difficulty resides in the need to administer three or more doses i.v. to achieve sufficient immunity. Strategies to reduce the number of RAS doses are therefore desirable. Here we used mice to model human immune responses to a single, suboptimal weight-normalized RAS dose administered i.v. followed by subunit vaccination to amplify liver-stage–specific memory CD8 T cells. RAS+subunit prime-boost regimens increased the numbers of liver-stage–specific memory CD8 T cells to a level greater than is present after one RAS vaccination. Both i.v. and i.m. subunit vaccine delivery induced immunity in mice, and many vaccinated mice completely cleared liver infection. These findings are particularly relevant to human vaccine developm...