Divergent fates of antigen-specific CD8+ T cell clones in mice with acute leukemia

Xiufen Chen, Brendan W. MacNabb, Blake Flood, Bruce R. Blazar, Justin Kline

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The existence of a dysfunctional CD8+ T cell state in cancer is well established. However, the degree to which CD8+ T cell fates are influenced by the context in which they encounter cognate tumor antigen is less clear. We previously demonstrated that CD8+ T cells reactive to a model leukemia antigen were deleted by antigen cross-presenting type 1 conventional dendritic cells (cDC1s). Here, through a study of T cell receptor (TCR) transgenic CD8+ T cells (TCRTg101) reactive to a native C1498 leukemia cell antigen, we uncover a different mode of T cell tolerance in which TCRTg101 undergo progressive expansion and differentiation into an exhausted state. Antigen encounter by TCRTg101 requires leukemia cell major histocompatibility complex (MHC)-I expression and is independent of DCs, implying that leukemia cells directly mediate the exhausted TCRTg101 phenotype. Collectively, our data reveal that leukemia antigens are presented to CD8+ T cells via discrete pathways, leading to distinct tolerant states.

Original languageEnglish (US)
Article number109991
JournalCell reports
Volume37
Issue number6
DOIs
StatePublished - Nov 9 2021

Bibliographical note

Funding Information:
The authors would like to acknowledge the University of Chicago Transgenics/ES Cell Technology Mouse Core Facility and, in particular, Linda Degenstein for assistance in generating Tg101 mice. We are also grateful to Marlieke Jongsma, PhD, for generating K b−/− and D b−/− C1498 cell lines. This work was funded by the Janet Rowley Discovery Fund to J.K. and grants R01 HL56067 and R37 AI 34495 to B.R.B.

Funding Information:
The authors would like to acknowledge the University of Chicago Transgenics/ES Cell Technology Mouse Core Facility and, in particular, Linda Degenstein for assistance in generating Tg101 mice. We are also grateful to Marlieke Jongsma, PhD, for generating Kb?/? and Db?/? C1498 cell lines. This work was funded by the Janet Rowley Discovery Fund to J.K. and grants R01 HL56067 and R37 AI 34495 to B.R.B. Conceptualization, X.C. B.W.M. and J.K.; methodology, X.C.; investigation X.C.; formal analysis, X.C. B.W.M. B.F. and J.K.; writing ? original draft, X.C. and J.K.; writing ? review & editing, X.C. B.W.M. B.R.B. and J.K.; funding acquisition, J.K. and B.R.B.; resources, B.R.B and J.K.; supervision, J.K. The authors declare no competing interests.

Publisher Copyright:
© 2021 The Author(s)

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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