Proliferating Transitory T Cells with an Effector-like Transcriptional Signature Emerge from PD-1+ Stem-like CD8+ T Cells during Chronic Infection

Immunity. 2019 Dec 17;51(6):1043-1058.e4. doi: 10.1016/j.immuni.2019.11.002. Epub 2019 Dec 3.


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 CD101-Tim3+ cells that later converted into CD101+ Tim3+ cells. Recently generated CD101-Tim3+ 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 CD101-Tim3+ CD8+ T cells, suggesting that these newly generated transitional cells play a critical role in PD-1-based immunotherapy.

Keywords: CD101; CD8(+) T cells; CX3CR1; LCMV; PD-1; T cell differentiation; checkpoint blockade; chronic viral infection; exhaustion; immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • Biomarkers / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CX3C Chemokine Receptor 1 / genetics
  • CX3C Chemokine Receptor 1 / metabolism
  • Female
  • Granzymes / genetics
  • Granzymes / metabolism
  • Hepatitis A Virus Cellular Receptor 2 / biosynthesis
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism*


  • Antigens, CD
  • Biomarkers
  • CX3C Chemokine Receptor 1
  • Cd101 protein, mouse
  • Cx3cr1 protein, mouse
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Granzymes
  • Gzmb protein, mouse