Immunity
Volume 51, Issue 6, 17 December 2019, Pages 1043-1058.e4
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Article
Proliferating Transitory T Cells with an Effector-like Transcriptional Signature Emerge from PD-1+ Stem-like CD8+ T Cells during Chronic Infection

https://doi.org/10.1016/j.immuni.2019.11.002Get rights and content
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Highlights

  • CX3CR1+ CD8+ T cells are recent progeny of stem-like cells in chronic infection

  • CX3CR1+ cells differentiate to a dysfunctional state marked by CD101 expression

  • Transitory CX3CR1+ cells express effector molecules and contribute to viral control

  • PD-1 pathway blockade increases the number of antigen-specific transitory cells

Summary

T cell dysfunction is a characteristic feature of chronic viral infection and cancer. Recent studies in chronic lymphocytic choriomeningitis virus (LCMV) infection have defined a PD-1+ Tcf-1+ CD8+ T cell subset capable of self-renewal and differentiation into more terminally differentiated cells that downregulate Tcf-1 and express additional inhibitory molecules such as Tim3. Here, we demonstrated that expression of the glycoprotein CD101 divides this terminally differentiated population into two subsets. Stem-like Tcf-1+ CD8+ T cells initially differentiated into a transitory population of CD101Tim3+ cells that later converted into CD101+ Tim3+ cells. Recently generated CD101Tim3+ cells proliferated in vivo, contributed to viral control, and were marked by an effector-like transcriptional signature including expression of the chemokine receptor CX3CR1, pro-inflammatory cytokines, and granzyme B. PD-1 pathway blockade increased the numbers of CD101Tim3+ CD8+ T cells, suggesting that these newly generated transitional cells play a critical role in PD-1-based immunotherapy.

Keywords

CD8+ T cells
exhaustion
immunotherapy
PD-1
LCMV
chronic viral infection
CX3CR1
CD101
checkpoint blockade
T cell differentiation

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