IL-18BP mediates the balance between protective and pathological immune responses to Toxoplasma gondii
Open accessAbstract
SUMMARY Interleukin-18 (IL-18) promotes natural killer (NK) and T cell production of interferon (IFN)-γ, a key factor in resistance to Toxoplasma gondii, but previous work has shown a limited role for endogenous IL-18 in control of this parasite. Although infection with T. gondii results in release of IL-18, the production of IFN-γ induces high levels of the IL-18 binding protein (IL-18BP). Antagonism of IL-18BP with a “decoy-to-the-decoy” (D2D) IL-18 construct that does not signal but rather binds IL-18BP results in enhanced innate lymphoid cell (ILC) and T cell responses and improved parasite control. In addition, the use of IL-18 resistant to IL-18BP (“decoy-resistant” IL-18 [DR-18]) is more effective than exogenous IL-18 at promoting innate resistance to infection. DR-18 enhances CD4+ T cell production of IFN-γ but results in CD4+ T cell-mediated pathology. Thus, endogenous IL-18BP restrains aberrant immune pathology, and this study highlights strategies that can be used to tune this regulatory pathway for optimal anti-pathogen responses.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
TLR4 signaling is key in driving proinflammatory responses associated with COVID-19 and contributes to an increased Th1-type immune response because IL-18 (and IL-1β) strongly induces IFNs.
“TLR4 signaling is key in driving proinflammatory responses associated with COVID-19 and contributes to an increased Th1-type immune response because IL-18 (and IL-1 β ) strongly induces IFNs. 143-145”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [145]
The Introduction (p. 2) says IL-18 induces IFNγ production by NK and T cells and promotes Th1 immunity. The paper does not establish the claimed role of TLR4 signaling in COVID-19 or say that IL-1β strongly induces interferons; its findings concern Toxoplasma gondii. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIL-18 strongly drives Th1 immune responses, but in BALB/c mice, this produces a mixed Th1/Th2 response that promotes fibrosis and DCM rather than a classical STAT-driven Th1 response.
“IL-18, originally named IFNγ -inducing factor, strongly drives Th1 immune responses, 143-145 but in BALB/c mice, this produces a mixed Th1/Th2 response that promotes fibrosis and DCM rather than a classical STAT-driven Th1 respo nse. 115,146,160,165”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [145]
The citation is attached to the claim about BALB/c mice, a mixed Th1/Th2 response, fibrosis, and DCM. The Experimental Model (p. 11) identifies B6 and Rag1−/− mice, while the Discussion (p. 9) describes liver pathology; neither passage addresses the claimed BALB/c cardiac outcome. Searches for BALB/c, fibrosis, DCM, and STAT found no supporting passage in our copy. (LLM, conf=0.77)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Defective NK Cell Activity and Th1 Response in IL-18–Deficient Mice
Takeda, K., Tsutsui, H., Yoshimoto, T., Adachi, O., Yoshida, N., Kishimoto, T., Okamura, H., Nakanishi, K., & Akira, S. (1998) · Immunity · doi:10.1016/s1074-7613(00)80543-9 · Cited by 911 · see citing works
Rauch, I., Deets, K. A., Ji, D. X., von Moltke, J., Tenthorey, J. L., Lee, A. Y., Philip, N. H., Ayres, J. S., Brodsky, I. E., Gronert, K., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.03.016 · Cited by 403 · see citing works
Hunter, C. A., Chizzonite, R., & Remington, J. S. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.155.9.4347 · Cited by 245 · see citing works
Self-citationA role for IL‐18 in protective immunity against <i>Mycobacterium tuberculosis</i>
Schneider, B. E., Korbel, D., Hagens, K., Koch, M., Raupach, B., Enders, J., Kaufmann, S. H. E., Mittrücker, H., & Schaible, U. E. (2010) · European Journal of Immunology · doi:10.1002/eji.200939583 · Cited by 115 · see citing works
Wilson, D. C., Grotenbreg, G. M., Liu, K., Zhao, Y., Frickel, E., Gubbels, M., Ploegh, H. L., & Yap, G. S. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1000815 · Cited by 96 · see citing works
Kinjo, Y., Kawakami, K., Uezu, K., Yara, S., Miyagi, K., Koguchi, Y., Hoshino, T., Okamoto, M., Kawase, Y., Yokota, K., et al. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.1.323 · Cited by 86 · see citing works
Sateriale, A., Gullicksrud, J. A., Engiles, J. B., McLeod, B. I., Kugler, E. M., Henao‐Mejia, J., Zhou, T., Ring, A. M., Brodsky, I. E., Hunter, C. A., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2007807118 · Cited by 69 · see citing works
Self-citationThe Toxoplasma gondii Peptide AS15 Elicits CD4 T Cells That Can Control Parasite Burden
Grover, H. S., Blanchard, N., Gonzãlez, F., Chan, S. W., Robey, E. A., & Shastri, N. (2012) · Infection and Immunity · doi:10.1128/iai.00425-12 · Cited by 66 · see citing works
Flagged first, then by citations
Research works printed but not linked: 5
- [11]11. Gullicksrud J, Sateriale A, Englies J, Gibson A, Shaw S, Hutchins Z, Martin L, Christian D, Taylor GA, Yamamoto M, et al. (2021). Cross-talk between enterocytes and innate - lymphoid cell drives early IFNγ -mediated control of Cryptosporidium. Preprint at bioRxiv. 10.1101/2021.03.13.435244. · DOI
- [19]19. Gazzinelli RT, Hieny S, Wynn TA, Wolf S, and Sher A (1993). Interleukin 12 is required for the T-lymphocyte-independent induction of interferon gamma by an intracellular parasite and induces resistance in T-cell-deficient hosts. Proc. Natl. Acad. Sci. USA 90, 6115-6119. [PubMed: 8100999]
- [32]32. LaRosa DF, Stumhofer JS, Gelman AE, Rahman AH, Taylor DK, Hunter CA, and Turka LA (2008). T cell expression of MyD88 is required for resistance to Toxoplasma gondii. Proc. Natl. Acad. Sci. USA 105, 3855-3860. [PubMed: 18308927]
- [49]49. Hurgin V, Novick D, and Rubinstein M (2002). The promoter of IL-18 binding protein: activation by an IFNγ -induced complex of IFN regulatory factor 1 and CCAAT/enhancer binding protein β . Proc. Natl. Acad. Sci. USA 99, 16957-16962. [PubMed: 12482935]
- [64]64. Freeman BE, Hammarlund E, Raué HP, and Slifka MK (2012). Regulation of innate CD8+ T-cell activation mediated by cytokines. Proc. Natl. Acad. Sci. USA 109, 9971-9976. [PubMed: 22665806]
Cited by
Sorted by citations
COVID-19, Myocarditis and Pericarditis
Fairweather, D., Beetler, D. J., Di Florio, D. N., Musigk, N., Heidecker, B., & Cooper, L. T. (2023) · Circulation Research · doi:10.1161/circresaha.123.321878 · Cited by 181 · see citing works
- Authors
- Clark, J. T., Weizman, O.-E., Aldridge, D. L., Shallberg, L. A., Eberhard, J., Lanzar, Z., Wasche, D., Huck, J. D., Zhou, T., Ring, A. M., & Hunter, C. A.
- Affiliations
- University of Pennsylvania (US)
- Yale University (US)
- Corresponding author
- Ring, Aaron M.
- Hunter, Christopher A.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2023-03
- Volume
- 42
- Issue
- 3
- Pages
- 112147
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC10131179
- OpenAlex
- W4321603836
- Cited by
- 20
- References
- 8
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 6 · 2023: 3
- FWCI
- 4.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Gabrielle's Angel Foundation for Cancer Research
- NIH (DP5OD023088)
- National Institute of Allergy and Infectious Diseases (5T32AI00753223, 5R01AI25563-05)
- Topics
- Life Sciences › Immunology and Microbiology › Parasitology › Toxoplasma gondii Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- IL-18BP, IL-18, Toxoplasma gondii, toxoplasmosis, interferon-gamma, innate lymphoid cells, CD4+ T cells, immunopathology, innate immunity, parasite resistance
- MeSH terms
- Animals, Humans, Immunity, Innate, Killer Cells, Natural, Toxoplasma, Toxoplasmosis, Animal, Interleukin-12, Interleukin-18, Intercellular Signaling Peptides and Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
