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

• Published in: PLoS pathogens Vol. 16; no. 8; p. e1008327
• Main Authors: Kongsomboonvech, Angel K, Rodriguez, Felipe, Diep, Anh L, Justice, Brandon M, Castallanos, Brayan E, Camejo, Ana, Mukhopadhyay, Debanjan, Taylor, Gregory A, Yamamoto, Masahiro, Saeij, Jeroen P J, Reese, Michael L, Jensen, Kirk D C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.08.2020; Public Library of Science (PLoS)
• Subjects: Animals; Antigen presentation; Antigens; Autophagy; Biology; Biology and Life Sciences; Bone marrow; Caspase-1; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - parasitology; Chronic infection; Disease transmission; Female; Host-parasite interactions; Immune system; Immunity; Immunology; Infections; Inflammasomes; Inflammasomes - immunology; Interferon-gamma - metabolism; Interleukin 1 receptors; Interleukin 12; Interleukin 18; Interleukin 2; Isoforms; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - immunology; Macrophages - parasitology; Medicine and Health Sciences; Mice; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Parasites; Pathogens; Pathways; Phenotypic variations; Phosphorylation; Protein transport; Proteins; Protozoa; Protozoan Proteins - genetics; Protozoan Proteins - metabolism; Research and Analysis Methods; Signal Transduction; Toxoplasma - immunology; Toxoplasma gondii; Toxoplasmosis, Animal - immunology; Toxoplasmosis, Animal - parasitology; Vacuoles - immunology; Vacuoles - metabolism; Vacuoles - parasitology; Veterinary colleges; Veterinary medicine; Virulence; Virulence - immunology; γ-Interferon; North Carolina; California; United States > US; Massachusetts
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1008327

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.