TY - JOUR
T1 - Vaccinia Virus Vectors Targeting Peptides for MHC Class II Presentation to CD4+ T Cells
AU - Hobbs, Samuel J.
AU - Harbour, Jake C.
AU - Yates, Phillip A.
AU - Ortiz, Diana
AU - Landfear, Scott M.
AU - Nolz, Jeffrey C.
N1 - Funding Information:
Received for publication September 3, 2019. Accepted for publication December 16, 2019. Address correspondence and reprint requests to: Jeffrey C. Nolz, Department of Molecular Microbiology and Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239. E-mail address: nolz@ohsu.edu ORCIDs: 0000-0002-4282-8813 (S.J.H.); 0000-0003-2485-3932 (J.C.H.); 0000-0003-2016-9789 (P.A.Y.); 0000-0001-6492-8842 (D.O.); 0000-0002-1643-6664 (S.M.L.). This work was supported by grants from the National Institutes of Health (R01-AI132404 [to J.C.N.] and T32-AI007472 [to S.J.H.]). S.J.H., J.C.H., P.A.Y., and J.C.N. designed and performed experiments and analyzed the data. P.A.Y., D.O., and S.M.L. provided reagents and expertise in experimental design and analysis using Leishmania infections. S.J.H. and J.C.N. wrote the manuscript. Abbreviations used in this article: Ii, MHC-II invariant chain; LAMP1, lysosomal-associated membrane protein 1; LCMV, lymphocytic choriomeningitis virus; MHC-I, MHC class I; MHC-II, MHC class II; PEPCK, phosphoenolpyruvate carboxykinase; VacV, vaccinia virus. This article is distributed under the terms of the CC BY 4.0 Unported license. Copyright © 2020 The Authors
Publisher Copyright:
Copyright © 2020 The Authors
PY - 2020/1/1
Y1 - 2020/1/1
N2 - CD4+ helper T cells play important roles in providing help to B cells, macrophages, and cytotoxic CD8+ T cells, but also exhibit direct effector functions against a variety of different pathogens. In contrast to CD8+ T cells, CD4+ T cells typically exhibit broader specificities and undergo less clonal expansion during many types of viral infections, which often makes the identification of virus-specific CD4+ T cells technically challenging. In this study, we have generated recombinant vaccinia virus (VacV) vectors that target I-Ab–restricted peptides for MHC class II (MHC-II) presentation to activate CD4+ T cells in mice. Conjugating the lymphocytic choriomeningitis virus immunodominant epitope GP61–80 to either LAMP1 to facilitate lysosomal targeting or to the MHC-II invariant chain (Ii) significantly increased the activation of Ag-specific CD4+ T cells in vivo. Immunization with VacV-Ii-GP61–80 activated endogenous Ag-specific CD4+ T cells that formed memory and rapidly re-expanded following heterologous challenge. Notably, immunization of mice with VacV expressing an MHC-II–restricted peptide from Leishmania species (PEPCK335–351) conjugated to either LAMP1 or Ii also generated Ag-specific memory CD4+ T cells that underwent robust secondary expansion following a visceral leishmaniasis infection, suggesting this approach could be used to generate Ag-specific memory CD4+ T cells against a variety of different pathogens. Overall, our data show that VacV vectors targeting peptides for MHC-II presentation is an effective strategy to activate Ag-specific CD4+ T cells in vivo and could be used to study Ag-specific effector and memory CD4+ T cell responses against a variety of viral, bacterial, or parasitic infections. ImmunoHorizons, 2020, 4: 1–13.
AB - CD4+ helper T cells play important roles in providing help to B cells, macrophages, and cytotoxic CD8+ T cells, but also exhibit direct effector functions against a variety of different pathogens. In contrast to CD8+ T cells, CD4+ T cells typically exhibit broader specificities and undergo less clonal expansion during many types of viral infections, which often makes the identification of virus-specific CD4+ T cells technically challenging. In this study, we have generated recombinant vaccinia virus (VacV) vectors that target I-Ab–restricted peptides for MHC class II (MHC-II) presentation to activate CD4+ T cells in mice. Conjugating the lymphocytic choriomeningitis virus immunodominant epitope GP61–80 to either LAMP1 to facilitate lysosomal targeting or to the MHC-II invariant chain (Ii) significantly increased the activation of Ag-specific CD4+ T cells in vivo. Immunization with VacV-Ii-GP61–80 activated endogenous Ag-specific CD4+ T cells that formed memory and rapidly re-expanded following heterologous challenge. Notably, immunization of mice with VacV expressing an MHC-II–restricted peptide from Leishmania species (PEPCK335–351) conjugated to either LAMP1 or Ii also generated Ag-specific memory CD4+ T cells that underwent robust secondary expansion following a visceral leishmaniasis infection, suggesting this approach could be used to generate Ag-specific memory CD4+ T cells against a variety of different pathogens. Overall, our data show that VacV vectors targeting peptides for MHC-II presentation is an effective strategy to activate Ag-specific CD4+ T cells in vivo and could be used to study Ag-specific effector and memory CD4+ T cell responses against a variety of viral, bacterial, or parasitic infections. ImmunoHorizons, 2020, 4: 1–13.
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U2 - 10.4049/immunohorizons.1900070
DO - 10.4049/immunohorizons.1900070
M3 - Article
AN - SCOPUS:85107021013
VL - 4
SP - 1
EP - 13
JO - ImmunoHorizons
JF - ImmunoHorizons
SN - 2573-7732
IS - 1
ER -