Citation: El 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 Academic Editor: Jianxuan Wu Received: 17 July 2023 Revised: 26 August 2023 Accepted: 1 September 2023 Published: 14 September 2023 Copyright: © 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 (https:// creativecommons.org/licenses/by/ 4.0/). Article CD4 + T Cell Responses to Toxoplasma gondii Are a Double-Edged Sword Kamal El Bissati 1, * , Paulette A. Krishack 2 , Ying Zhou 3 , Christopher R. Weber 2 , Joseph Lykins 3,4 , Dragana Jankovic 5 , Karen L. Edelblum 6,7 , Laura Fraczek 3 , Harshita Grover 8 , Aziz A. Chentoufi 9 , Gurminder Singh 2 , Catherine Reardon 2 , J. P. Dubey 10 , Steve Reed 11 , Jeff Alexander 12 , John Sidney 13 , Alessandro Sette 13 , Nilabh Shastri 8 and Rima McLeod 3 1 Institute of Molecular Engineering, University of Chicago Medical Center, Chicago, IL 60637, USA 2 Department of Pathology, University of Chicago, Chicago, IL 60637, USA; pkrishack@gmail.com (P.A.K.); cweber@bsd.uchicago.edu (C.R.W.); gsingh@bwh.harvard.edu (G.S.); reardon@uchicago.edu (C.R.) 3 Department of Ophthalmology and Visual Sciences, University of Chicago, Chicago, IL 60637, USA; yzhou@bsd.uchicago.edu (Y.Z.); joseph.lykins@bmc.org (J.L.); laura.fraczek@gmail.com (L.F.); rmcleod@bsd.uchicago.edu (R.M.) 4 Department of Emergency Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02215, USA 5 Immunoparasitology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; djankovic@niaid.nih.gov 6 Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; karen.edelblum@mssm.edu 7 Center for Immunity and Inflammation, Laboratory Medicine, Department of Pathology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA 8 Division of Immunology and Pathogenesis, Department of Molecular and Cellular Biology, University of California, Berkeley, CA 94720, USA; harshita.grover@slalom.com (H.G.); nshastr3@jhmi.edu (N.S.) 9 Department of Medical Microbiology, Faculty of Health Sciences, University of Pretoria, Pretoria 0028, South Africa; achentou@uwo.ca 10 Animal Parasitic Diseases Laboratory, Beltsville Agricultural Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD 20705, USA 11 Infectious Diseases Research Institute, 1616 Eastlake Ave E #400, Seattle, WA 98102, USA; steven.reed@hdt.bio 12 PaxVax, 3985-A Sorrento Valley Blvd, San Diego, CA 92121, USA; jalexander4469@outlook.com 13 La Jolla Institute of Allergy and Immunology, 9420 Athena Cir, La Jolla, CA 92037, USA; jsidney@lji.org (J.S.); alex@lji.org (A.S.) * Correspondence: kelbissati@uchicago.edu Abstract: 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 cell- eliciting 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. Keywords: Toxoplasma gondii; HLA-A*11:01; vaccine; TLR4; CD4 + T cells 1. Introduction Toxoplasma gondii infection is devastating to the host and causes damage to eyes or central nervous system (CNS), resulting in loss of sight, disability, and death. Immunocom- promised individuals, including those with HIV/AIDS, and congenitally infected babies Vaccines 2023, 11, 1485. https://doi.org/10.3390/vaccines11091485 https://www.mdpi.com/journal/vaccines