ILC1-derived IFN-γ mediates cDC1-dependent host resistance againstToxoplasma gondii

Abstract

Host resistance against intracellular pathogens requires a rapid IFN- mediated immune response. We reveal that T-bet-dependent production of IFN- is essential for the maintenance of inflammatory DCs at the site of infection with a common protozoan parasite, Toxoplasma gondii. A detailed analysis of the cellular sources for T-bet-dependent IFN- identified that ILC1s, but not NK or T H 1 cells, were involved in the regulation of inflammatory DCs via IFN-.Mechanistically, we established that T-bet dependent ILC1-derived IFN- is critical for the induction of IRF8, an essential transcription factor for cDC1s. Failure to upregulate IRF8 in DCs resulted in acute susceptibility to T. gondii infection. Our data identifies that ILC1-derived IFN- is indispensable for host resistance against intracellular infection via maintaining IRF8+ inflammatory DCs at the site of infection. Author SummaryMounting a robust type I innate immune response is essential for resistance against numerous intracellular pathogens. The type I immune response is characterized by the production of IFN-, a central cytokine required for multiple non-redundant effector functions against bacterial, viral, and parasitic pathogens. Previous work has shown that group 1 innate lymphocyte cells (ILC1s) together with NK and CD4+ T cells play an indispensable IFN- mediated protective role against Toxoplasma gondii infection; yet, the pathway of how IFN- produced by ILC1s defend against T. gondii remains unknown. In this work we identified that early production of IFN- by ILC1 is essential for maintaining dendritic cells (DCs) during infection. Mechanistically, we reveal that ILC1-derived IFN- is indispensable for inducing the transcription factor IRF8 that is critical for sustaining inflammatory DCs. Finally, we demonstrate that IRF8+ DCs are critical for parasite elimination.

IL-33 promotes innate lymphoid cell-dependent IFN-γ production required for innate immunity to Toxoplasma gondii

“…For example, these models were important to identify the role of IL-12 in promoting NK cell production of IFN-γ required for innate resistance to Listeria monocytogenes and T. gondii ( Bancroft et al, 1991 ; Tripp et al, 1993 ; Hunter et al, 1993 ). It is now appreciated that NK cells and ILC1 populations are both relevant sources of IFN-γ that contribute to the control of T. gondii ( Park et al, 2019 ; Weizman et al, 2017 ; López-Yglesias et al, 2020 ). Although IL-1 and IL-18 synergize with IL-12 to promote NK cell production of IFN-γ ( Hunter et al, 1995a ; Cai et al, 2000 ; Kearley et al, 2015 ), the role of endogenous IL-1 during toxoplasmosis is secondary to those of IL-12 ( Hitziger et al, 2005 ; Hunter et al, 1995a ; Melchor et al, 2020 ), and endogenous IL-18 is not required for parasite control but rather contributes to the immune pathology that can accompany this infection ( Cai et al, 2000 ; Yap et al, 2001 ; Vossenkämper et al, 2004 ; Ewald et al, 2014 ; Gorfu et al, 2014 ).…”

“…For example, these models were important to identify the role of IL-12 in promoting NK cell production of IFN- required for innate resistance to Listeria monocytogenes and T. gondii [29]- [31]. It is now appreciated that NK cells and ILC1 populations are both relevant sources of IFN- that contribute to control of T. gondii [32]- [34].…”

“One Health” Goal: Novel Preliminary Study on Putative Pig Immuno-Genetic Resistance to <em>Toxoplasma gondii</em> and Serologi-Cal Survey in Central Italy Regions

“…To date, it is also not completely clear which TLRs contribute to the parasite recognition and internalization in intermediate hosts, such in pigs, [31] and the immunological pathways have yet to be partly explored. Anyway, the study of Lopez-Yglesias et al, 2019 [36] demonstrated, in murine models, that in the absence of TLR11, as in the case of pigs, the production of the caspase-1-dependent cytokine IL-18 was sufficient and necessary for CD4+ T cellderived IFN-γ responses in T. gondii infection.…”

“…Furthermore, it was important to carry out the genetic study after ensuring that the candidate gene was present and expressed [31], in the tissue matrix (diaphragmatic muscle) used for this type of investigation [34]. Concerning the interaction hostparasite, T. gondii recognition by receptors (like TLRs) is certainly necessary for the production of IL-12 and IL-18 by dendritic cells (DCs), thus for a rapid and robust CD4+ T helper 1 (Th1) response leading to the release of IFN-γ [35,36]. When T. gondii infection is ongoing both IL-18 and IFN-γ cytokines play a pivotal role in host resistance to the parasite [37,38].…”

Transferrin Receptor 1 is Required for CD4+ T Cell Iron-Dependent Response During AcuteToxoplasma gondiiInfection

“…Immunity to T. gondii is triggered by recognition of the parasite by TLR4 and 11 and the production of the proinflammatory cytokine IL-12 (16)(17)(18)(19)(20). IL-12 activates group 1 Innate Lymphoid Cells including Natural Killer (NK) Cells and ILC1 for the initial production of IFNg required for early control of T. gondii (21)(22)(23). After presentation of T. gondii antigens to T cells by CD8a+ Dendritic cells, both CD4+ and CD8+ T cells mount a robust response producing high levels of IFNg (24).…”