| First Author | Kongsomboonvech AK | Year | 2020 |
| Journal | PLoS Pathog | Volume | 16 |
| Issue | 8 | Pages | e1008327 |
| PubMed ID | 32853276 | Mgi Jnum | J:329681 |
| Mgi Id | MGI:6796734 | Doi | 10.1371/journal.ppat.1008327 |
| Citation | Kongsomboonvech AK, et al. (2020) Naive CD8 T cell IFNgamma responses to a vacuolar antigen are regulated by an inflammasome-independent NLRP3 pathway and Toxoplasma gondii ROP5. PLoS Pathog 16(8):e1008327 |
| abstractText | Host resistance to Toxoplasma gondii relies on CD8 T cell IFNgamma 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 naive CD8 T cell IFNgamma responses to a vacuolar resident antigen of T. gondii, TGD057. Naive 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 IFNgamma. T57 IFNgamma 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 IFNgamma responses to parasite-infected BMDMs. Phenotypic variance between clades B, C, D, F, and A strains suggest T57 IFNgamma 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 IFNgamma 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 IFNgamma responses to parasite-infected ASC, caspase-1/11, and gasdermin D deficient cells. Moreover, IFNgamma 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 IFNgamma responses to a vacuolar antigen. |
