@article{94bf157570224b0c8acff444f8ba2db5,
title = "Negative Co-stimulation Constrains T Cell Differentiation by Imposing Boundaries on Possible Cell States",
abstract = "Co-stimulation regulates T cell activation, but it remains unclear whether co-stimulatory pathways also control T cell differentiation. We used mass cytometry to profile T cells generated in the genetic absence of the negative co-stimulatory molecules CTLA-4 and PD-1. Our data indicate that negative co-stimulation constrains the possible cell states that peripheral T cells can acquire. CTLA-4 imposes major boundaries on CD4+ T cell phenotypes, whereas PD-1 subtly limits CD8+ T cell phenotypes. By computationally reconstructing T cell differentiation paths, we identified protein expression changes that underlied the abnormal phenotypic expansion and pinpointed when lineage choice events occurred during differentiation. Similar alterations in T cell phenotypes were observed after anti-CTLA-4 and anti-PD-1 antibody blockade. These findings implicate negative co-stimulation as a key regulator and determinant of T cell differentiation and suggest that checkpoint blockade might work in part by altering the limits of T cell phenotypes.",
author = "Wei, {Spencer C.} and Roshan Sharma and Anang, {Nana Ama A.S.} and Levine, {Jacob H.} and Yang Zhao and Mancuso, {James J.} and Manu Setty and Padmanee Sharma and Jing Wang and Dana Pe'er and Allison, {James P.}",
note = "Funding Information: We thank Duncan Mak for providing expert advice in mass-cytometry analysis, members of the Allison and Pe{\textquoteright}er labs for helpful discussions, and Caitlin Trasande for critical reading. Mass cytometry was performed at the MD Anderson Cancer Center (MDACC) Flow Cytometry and Cellular Imaging Core Facility, transgenic mouse lines were generated with the MDACC Genetically Engineered Mouse Facility, and sequencing was performed at the MDACC Sequencing and Microarray Facility, all of which are in part funded by National Cancer Institute Cancer Center Support Grant (CCSG) P30CA16672 . This work was supported by a grant from Cancer Prevention and Research in Texas to J.P.A. ( R1203 ), the MDACC CCSG Bioinformatics Shared Resource , NIH grants to D.P. ( DP1-HD084071 and R01CA164729 ), and a MSK Cancer Center Support Grant/Core Grant to D.P. ( P30CA008748 ). S.C.W. was an MD Anderson Cancer Center Odyssey postdoctoral fellow. Funding Information: We thank Duncan Mak for providing expert advice in mass-cytometry analysis, members of the Allison and Pe'er labs for helpful discussions, and Caitlin Trasande for critical reading. Mass cytometry was performed at the MD Anderson Cancer Center (MDACC) Flow Cytometry and Cellular Imaging Core Facility, transgenic mouse lines were generated with the MDACC Genetically Engineered Mouse Facility, and sequencing was performed at the MDACC Sequencing and Microarray Facility, all of which are in part funded by National Cancer Institute Cancer Center Support Grant (CCSG) P30CA16672. This work was supported by a grant from Cancer Prevention and Research in Texas to J.P.A. (R1203), the MDACC CCSG Bioinformatics Shared Resource, NIH grants to D.P. (DP1-HD084071 and R01CA164729), and a MSK Cancer Center Support Grant/Core Grant to D.P. (P30CA008748). S.C.W. was an MD Anderson Cancer Center Odyssey postdoctoral fellow. S.C.W. and J.P.A. conceived the project and wrote the manuscript. R.S. J.H.L. and D.P. conceived and developed computational methods. S.C.W. R.S. N.-A.A.S.A. Y.Z. and J.H.L. analyzed data. S.C.W. R.S. J.H.L. M.S. J.J.M. P.S. J.W. D.P. and J.P.A. interpreted data. S.C.W. is an employee of Spotlight Therapeutics. J.P.A. is a co-director of the Parker Institute for Cancer Immunotherapy. J.P.A. has ownership interest in Jounce Therapeutics, Neon Therapeutics, Forty-Seven, Codiak, ImaginAb, Marker Therapeutics, Tvardi Therapeutics, Constellation Pharmaceuticals, BioAlta, Polaris Pharmaceuticals, Hummingbird Bioscience, Merck, Bristol-Myers Squibb (BMS), Amgen, and Apricity Therapeutics; is a scientific advisory board member and consultant for Jounce, BioAtla, Neon, Codiak, Tvardi, Amgen, Forty-Seven, ImaginAb, Marker, Apricity, Polaris, ImaginAB, BMS, Merck, and Hummingbird; and has received royalties from intellectual property licensed to BMS, Merck, and Jounce. P.S. has ownership interest in Jounce, Neon, Constellation, Oncolytics Biotech, Merck, BioMx, BioAtla, Forty-Seven, Apricity, Polaris, Marker, ImaginAB, Hummingbird, Pieris Pharmaceuticals, Amgen, and Codiak; is a scientific advisory board member and consultant for Jounce, Constellation, Neon, BioAtla, Pieris, Oncolytics, Merck, BioMx, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, Hummingbird, AstraZeneca, Amgen, GlaxoSmithKline (GSK), and BMS; and is a co-founder and advisor of Jounce Therapeutics. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = apr,
day = "16",
doi = "10.1016/j.immuni.2019.03.004",
language = "English (US)",
volume = "50",
pages = "1084--1098.e10",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "4",
}