El Bissati, KamalKrishack, Paulette A.Zhou, YingWeber, Christopher R.Lykins, JosephJankovic, DraganaEdelblum, Karen L.Fraczek, LauraGrover, HarshitaChentoufi, Aziz AlamiSingh, GurminderReardon, CatherineDubey, J.P.Reed, SteveAlexander, JeffSidney, JohnSette, AlessandroShastri, NilabhMcLeod, Rima2023-12-012023-12-012023-09-14El Bissati, K.; Krishack, P.A.; Zhou, Y.;Weber, C.R.; Lykins, J.; Jankovic, D.; Edelblum, K.L.; Fraczek, L.; Grover, H.; Chentoufi, A.A.; et al. CD4+ T Cell Responses to Toxoplasma gondii Are a Double-Edged Sword. Vaccines 2023, 11, 1485. https://DOI.org/10.3390/vaccines11091485.2076-393X2076-393X (online)10.3390/vaccines11091485http://hdl.handle.net/2263/93584SUPPLEMENTARY MATERIALS : FIGURE S1: Cartoon model showing the conceptual advance provided by this work.DATA AVAILABILITY STATEMENT : Data sharing is not applicable to this article.CD4+ T cells have been found to play critical roles in the control of both acute and chronic Toxoplasma infection. Previous studies identified a protective role for the Toxoplasma CD4+ T celleliciting peptide AS15 (AVEIHRPVPGTAPPS) in C57BL/6J mice. Herein, we found that immunizing mice with AS15 combined with GLA-SE, a TLR-4 agonist in emulsion adjuvant, can be either helpful in protecting male and female mice at early stages against Type I and Type II Toxoplasma parasites or harmful (lethal with intestinal, hepatic, and spleen pathology associated with a storm of IL6). Introducing the universal CD4+ T cell epitope PADRE abrogates the harmful phenotype of AS15. Our findings demonstrate quantitative and qualitative features of an effective Toxoplasma-specific CD4+ T cell response that should be considered in testing next-generation vaccines against toxoplasmosis. Our results also are cautionary that individual vaccine constituents can cause severe harm depending on the company they keep.en© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.Toxoplasma gondiiHLA-A*11:01VaccineTLR4CD4+ T cellsArticle