Effector and stem-like memory cell fates are imprinted in distinct lymph node niches directed by CXCR3 ligands

Nat Immunol. 2021 Apr;22(4):434-448. doi: 10.1038/s41590-021-00878-5. Epub 2021 Mar 1.

Abstract

T cells dynamically interact with multiple, distinct cellular subsets to determine effector and memory differentiation. Here, we developed a platform to quantify cell location in three dimensions to determine the spatial requirements that direct T cell fate. After viral infection, we demonstrated that CD8+ effector T cell differentiation is associated with positioning at the lymph node periphery. This was instructed by CXCR3 signaling since, in its absence, T cells are confined to the lymph node center and alternatively differentiate into stem-like memory cell precursors. By mapping the cellular sources of CXCR3 ligands, we demonstrated that CXCL9 and CXCL10 are expressed by spatially distinct dendritic and stromal cell subsets. Unlike effector cells, retention of stem-like memory precursors in the paracortex is associated with CCR7 expression. Finally, we demonstrated that T cell location can be tuned, through deficiency in CXCL10 or type I interferon signaling, to promote effector or stem-like memory fates.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Arenaviridae Infections / genetics
  • Arenaviridae Infections / immunology
  • Arenaviridae Infections / metabolism*
  • Arenaviridae Infections / virology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / virology
  • Cell Differentiation*
  • Cell Lineage
  • Cells, Cultured
  • Chemokine CXCL10 / genetics
  • Chemokine CXCL10 / metabolism*
  • Chemokine CXCL9 / genetics
  • Chemokine CXCL9 / metabolism*
  • Chemotaxis, Leukocyte
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • Host-Pathogen Interactions
  • Immunologic Memory*
  • Interferon Type I / metabolism
  • Ligands
  • Lymph Nodes / immunology
  • Lymph Nodes / metabolism*
  • Lymph Nodes / virology
  • Lymphocytic choriomeningitis virus / immunology
  • Lymphocytic choriomeningitis virus / pathogenicity
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Precursor Cells, T-Lymphoid / immunology
  • Precursor Cells, T-Lymphoid / metabolism*
  • Precursor Cells, T-Lymphoid / virology
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / metabolism
  • Receptors, CCR7 / metabolism
  • Receptors, CXCR3 / genetics
  • Receptors, CXCR3 / metabolism*
  • Signal Transduction
  • Stem Cell Niche
  • Stromal Cells / immunology
  • Stromal Cells / metabolism

Substances

  • Ccr7 protein, mouse
  • Chemokine CXCL10
  • Chemokine CXCL9
  • Cxcl10 protein, mouse
  • Cxcl9 protein, mouse
  • Cxcr3 protein, mouse
  • Ifnar1 protein, mouse
  • Interferon Type I
  • Ligands
  • Receptors, CCR7
  • Receptors, CXCR3
  • Receptor, Interferon alpha-beta