Hyaluronan-binding by CD44 reduces the memory potential of activated murine CD8 T cells

Eur J Immunol. 2018 May;48(5):803-814. doi: 10.1002/eji.201747263. Epub 2018 Jan 19.

Abstract

Expansion and death of effector CD8 T cells are regulated to limit immunopathology and cells that escape contraction go on to generate immunological memory. CD44, a receptor for the extracellular matrix component hyaluronan, is a marker of activated and memory T cells. Here, we show with a murine model that the increase in CD44 expression and hyaluronan binding induced upon CD8 T cell activation was proportional to the strength of TCR engagement, thereby identifying the most strongly activated T cells. When CD44-/- and CD44+/+ OT-I CD8 T cells were adoptively transferred into mice challenged with Listeria-OVA, there was a slight increase in the percentage of CD44+/+ cells at the effector site. However, CD44+/+ cells were out-competed by CD44-/- cells after the contraction phase in the lymphoid tissues, and the CD44-/- cells preferentially formed more memory cells. The hyaluronan-binding CD44+/+ CD8 effector T cells showed increased pAkt expression, higher glucose uptake, and were more susceptible to cell death during the contraction phase compared to non-binding CD44+/+ and CD44-/- OT-I CD8 T cells, suggesting that CD44 and its engagement with hyaluronan skews CD8 T cells toward a terminal effector differentiation state that reduces their ability to form memory cells.

Keywords: CD44; Hyaluronan; Memory CD8 T cell formation; T cell contraction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / transplantation
  • Cell Differentiation / immunology
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • Hyaluronic Acid / metabolism*
  • Immunologic Memory / immunology*
  • Listeria monocytogenes / immunology
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Ovalbumin / immunology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Antigen, T-Cell / immunology

Substances

  • Cd44 protein, mouse
  • Hyaluronan Receptors
  • Receptors, Antigen, T-Cell
  • Hyaluronic Acid
  • Ovalbumin
  • Proto-Oncogene Proteins c-akt