CD45 pre-exclusion from the tips of T cell microvilli prior to antigen recognition

Nat Commun. 2021 Jun 23;12(1):3872. doi: 10.1038/s41467-021-23792-8.

Abstract

The tyrosine phosphatase CD45 is a major gatekeeper for restraining T cell activation. Its exclusion from the immunological synapse (IS) is crucial for T cell receptor (TCR) signal transduction. Here, we use expansion super-resolution microscopy to reveal that CD45 is mostly pre-excluded from the tips of microvilli (MV) on primary T cells prior to antigen encounter. This pre-exclusion is diminished by depleting cholesterol or by engineering the transmembrane domain of CD45 to increase its membrane integration length, but is independent of the CD45 extracellular domain. We further show that brief MV-mediated contacts can induce Ca2+ influx in mouse antigen-specific T cells engaged by antigen-pulsed antigen presenting cells (APC). We propose that the scarcity of CD45 phosphatase activity at the tips of MV enables or facilitates TCR triggering from brief T cell-APC contacts before formation of a stable IS, and that these MV-mediated contacts represent the earliest step in the initiation of a T cell adaptive immune response.

Publication types

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

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology*
  • Antigen-Presenting Cells / metabolism
  • Cells, Cultured
  • Female
  • HEK293 Cells
  • Humans
  • Jurkat Cells
  • Leukocyte Common Antigens / genetics
  • Leukocyte Common Antigens / immunology*
  • Leukocyte Common Antigens / metabolism
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microvilli / immunology*
  • Microvilli / metabolism
  • Phosphorylation / immunology
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / immunology
  • Protein Tyrosine Phosphatases / metabolism
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • Receptors, Antigen, T-Cell
  • Leukocyte Common Antigens
  • Protein Tyrosine Phosphatases