Negative Co-stimulation Constrains T Cell Differentiation by Imposing Boundaries on Possible Cell States

Spencer C. Wei, Roshan Sharma, Nana Ama A.S. Anang, Jacob H. Levine, Yang Zhao, James J. Mancuso, Manu Setty, Padmanee Sharma, Jing Wang, Dana Pe'er, James P. Allison

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1084-1098.e10
JournalImmunity
Volume50
Issue number4
DOIs
StatePublished - Apr 16 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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  • Research Animal Support Facility

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