Naïve CD8 T cell IFNγ responses to a vacuolar antigen are regulated by an inflammasome-independent NLRP3 pathway and Toxoplasma gondii ROP5.

Autor: Kongsomboonvech AK; Department of Molecular and Cell Biology, University of California, Merced, Merced, California, United States of America., Rodriguez F; Department of Molecular and Cell Biology, University of California, Merced, Merced, California, United States of America., Diep AL; Department of Molecular and Cell Biology, University of California, Merced, Merced, California, United States of America., Justice BM; Department of Molecular and Cell Biology, University of California, Merced, Merced, California, United States of America., Castallanos BE; Department of Molecular and Cell Biology, University of California, Merced, Merced, California, United States of America., Camejo A; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America., Mukhopadhyay D; Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America., Taylor GA; Departments of Medicine; Molecular Genetics and Microbiology; and Immunology; and Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, North Carolina, United States of America.; Geriatric Research, Education, and Clinical Center, Durham VA Health Care System, Durham, North Carolina, United States of America., Yamamoto M; Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan., Saeij JPJ; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.; Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America., Reese ML; Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, Texas, United States of America., Jensen KDC; Department of Molecular and Cell Biology, University of California, Merced, Merced, California, United States of America.; Health Sciences Research Institute, University of California, Merced, Merced, California, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2020 Aug 27; Vol. 16 (8), pp. e1008327. Date of Electronic Publication: 2020 Aug 27 (Print Publication: 2020).
DOI: 10.1371/journal.ppat.1008327
Abstrakt: Host resistance to Toxoplasma gondii relies on CD8 T cell IFNγ responses, which if modulated by the host or parasite could influence chronic infection and parasite transmission between hosts. Since host-parasite interactions that govern this response are not fully elucidated, we investigated requirements for eliciting naïve CD8 T cell IFNγ responses to a vacuolar resident antigen of T. gondii, TGD057. Naïve TGD057 antigen-specific CD8 T cells (T57) were isolated from transnuclear mice and responded to parasite-infected bone marrow-derived macrophages (BMDMs) in an antigen-dependent manner, first by producing IL-2 and then IFNγ. T57 IFNγ responses to TGD057 were independent of the parasite's protein export machinery ASP5 and MYR1. Instead, host immunity pathways downstream of the regulatory Immunity-Related GTPases (IRG), including partial dependence on Guanylate-Binding Proteins, are required. Multiple T. gondii ROP5 isoforms and allele types, including 'avirulent' ROP5A from clade A and D parasite strains, were able to suppress CD8 T cell IFNγ responses to parasite-infected BMDMs. Phenotypic variance between clades B, C, D, F, and A strains suggest T57 IFNγ differentiation occurs independently of parasite virulence or any known IRG-ROP5 interaction. Consistent with this, removal of ROP5 is not enough to elicit maximal CD8 T cell IFNγ production to parasite-infected cells. Instead, macrophage expression of the pathogen sensors, NLRP3 and to a large extent NLRP1, were absolute requirements. Other members of the conventional inflammasome cascade are only partially required, as revealed by decreased but not abrogated T57 IFNγ responses to parasite-infected ASC, caspase-1/11, and gasdermin D deficient cells. Moreover, IFNγ production was only partially reduced in the absence of IL-12, IL-18 or IL-1R signaling. In summary, T. gondii effectors and host machinery that modulate parasitophorous vacuolar membranes, as well as NLR-dependent but inflammasome-independent pathways, determine the full commitment of CD8 T cells IFNγ responses to a vacuolar antigen.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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