T cell receptor-targeted immunotherapeutics drive selective in vivo HIV- and CMV-specific T cell expansion in humanized mice. J Clin Invest 2021 Dec 01;131(23)
Date
10/22/2021Pubmed ID
34673568Pubmed Central ID
PMC8631598DOI
10.1172/JCI141051Scopus ID
2-s2.0-85121153546 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
To delineate the in vivo role of different costimulatory signals in activating and expanding highly functional virus-specific cytotoxic CD8+ T cells, we designed synTacs, infusible biologics that recapitulate antigen-specific T cell activation signals delivered by antigen-presenting cells. We constructed synTacs consisting of dimeric Fc-domain scaffolds linking CD28- or 4-1BB-specific ligands to HLA-A2 MHC molecules covalently tethered to HIV- or CMV-derived peptides. Treatment of HIV-infected donor PBMCs with synTacs bearing HIV- or CMV-derived peptides induced vigorous and selective ex vivo expansion of highly functional HIV- and/or CMV-specific CD8+ T cells, respectively, with potent antiviral activities. Intravenous injection of HIV- or CMV-specific synTacs into immunodeficient mice intrasplenically engrafted with donor PBMCs markedly and selectively expanded HIV-specific (32-fold) or CMV-specific (46-fold) human CD8+ T cells populating their spleens. Notably, these expanded HIV- or CMV-specific CD8+ T cells directed potent in vivo suppression of HIV or CMV infections in the humanized mice, providing strong rationale for consideration of synTac-based approaches as a therapeutic strategy to cure HIV and treat CMV and other viral infections. The synTac platform flexibility supports facile delineation of in vivo effects of different costimulatory signals on patient-derived virus-specific CD8+ T cells, enabling optimization of individualized therapies, including HIV cure strategies.
Author List
Li M, Garforth SJ, O'Connor KE, Su H, Lee DM, Celikgil A, Chaparro RJ, Seidel RD, Jones RB, Arav-Boger R, Almo SC, Goldstein HAuthor
Ravit Boger MD Chief, Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntigen-Presenting Cells
Biological Products
CD8-Positive T-Lymphocytes
Cytomegalovirus
Cytomegalovirus Infections
HEK293 Cells
HIV Infections
HLA-A2 Antigen
Humans
Immunotherapy
In Vitro Techniques
Jurkat Cells
Leukocytes, Mononuclear
Ligands
Mice
Mice, SCID
Peptides
Receptors, Antigen, T-Cell
Spleen
T-Lymphocytes
T-Lymphocytes, Cytotoxic
