Studies on Immune Regulation in Toxoplasmosis

Sher, A.

Abstract

The overall aim of this project is to analyze the immune response to Toxoplasma gondi in order to define which cellular immune components and parasite target antigens are involved in the control of infection and its breakdown in immunocompromised hosts. Progress was made this year in the following areas: A. Analysis of Class I MHC presentation pathways and CD8+ cell target molecules utilized by T. gondii. Bone marrow macrophages were shown to process soluble T. gondii antigens for presentation to CD8+ T cells by an endogenous pathway. A preliminary analysis of the processed parasite proteins and CTL target peptide epitopes was performed. B. Role of cytokines in down-regulation of macrophage-mediated killing of T. gondii and T. cruzi. IL-10, IL-4 and TGF-~ were shown to down-regulate the intracellular killing of T. gondii by activated macrophage through the inhibition of nitrogen oxide production. Parallel results were found with a related intracellular parasite, Trypanosoma cruzi. C. Role of NK cells in the cytokine response to T. gondii. T. gondii was shown to trigger the T lymphocyte-independent production of IFN-gamma by NK cells. SCID mice depleted of NK cells were shown to be more susceptible to infection, and NK cells were shown to replace CD8+ cells as the primary effectors of immunity in vaccinated beta2-microglobulin- deficient mice.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Intramural Research (Z01)
• Project #: 1Z01AI000579-03
• Application #: 3790824
• Support Year: 3
• Fiscal Year: 1992

Institution

• Name: National Institute of Allergy and Infectious Diseases
• Country: United States

Publications

la Sala, Andrea; He, Jianping; Laricchia-Robbio, Leopoldo et al. (2009) Cholera toxin inhibits IL-12 production and CD8alpha+ dendritic cell differentiation by cAMP-mediated inhibition of IRF8 function. J Exp Med 206:1227-35

Goldszmid, Romina S; Coppens, Isabelle; Lev, Avital et al. (2009) Host ER-parasitophorous vacuole interaction provides a route of entry for antigen cross-presentation in Toxoplasma gondii-infected dendritic cells. J Exp Med 206:399-410

Plattner, Fabienne; Yarovinsky, Felix; Romero, Stephane et al. (2008) Toxoplasma profilin is essential for host cell invasion and TLR11-dependent induction of an interleukin-12 response. Cell Host Microbe 3:77-87

Feng, Carl G; Zheng, Lixin; Jankovic, Dragana et al. (2008) The immunity-related GTPase Irgm1 promotes the expansion of activated CD4+ T cell populations by preventing interferon-gamma-induced cell death. Nat Immunol 9:1279-87

Goldszmid, Romina S; Bafica, Andre; Jankovic, Dragana et al. (2007) TAP-1 indirectly regulates CD4+ T cell priming in Toxoplasma gondii infection by controlling NK cell IFN-gamma production. J Exp Med 204:2591-602

Trinchieri, Giorgio; Sher, Alan (2007) Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol 7:179-90

Jankovic, Dragana; Kullberg, Marika C; Feng, Carl G et al. (2007) Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J Exp Med 204:273-83

Amsen, Derk; Antov, Andrey; Jankovic, Dragana et al. (2007) Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. Immunity 27:89-99

Bertholet, Sylvie; Goldszmid, Romina; Morrot, Alexandre et al. (2006) Leishmania antigens are presented to CD8+ T cells by a transporter associated with antigen processing-independent pathway in vitro and in vivo. J Immunol 177:3525-33

Collazo, Carmen M; Sher, Alan; Meierovics, Anda I et al. (2006) Myeloid differentiation factor-88 (MyD88) is essential for control of primary in vivo Francisella tularensis LVS infection, but not for control of intra-macrophage bacterial replication. Microbes Infect 8:779-90