Physiologic and aberrant regulation of memory T-cell trafficking by the costimulatory molecule CD28

Blood. 2007 Apr 1;109(7):2968-77. doi: 10.1182/blood-2006-10-050724.

Abstract

Productive T-cell immunity requires both the activation and the migration of specific T cells to the antigenic tissue. The costimulatory molecule CD28 plays an essential role in the initiation of T-cell-mediated immunity. We investigated the possibility that CD28 may also regulate migration of primed T cells to target tissue. In vitro, CD28-mediated signals enhanced T-cell transendothelial migration, integrin clustering, and integrin-mediated migration. In vivo, T cells bearing a mutation in the CD28 cytoplasmic domain, which abrogates PI3K activation, displayed normal clonal expansion but defective localization to antigenic sites following antigenic rechallenge. Importantly, antibody-mediated CD28 stimulation led to unregulated memory T-cell migration to extra-lymphoid tissue, which occurred independently of T-cell receptor (TCR)-derived signals and homing-receptor expression. Finally, we provide evidence that CD28- and CTLA-4-mediated signals exert opposite effects on T-cell trafficking in vivo. These findings highlight a novel physiologic function of CD28 that has crucial implications for the therapeutic manipulation of this and other costimulatory molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Antigens
  • Antigens, CD / metabolism
  • Antigens, Differentiation / metabolism
  • CD28 Antigens / genetics
  • CD28 Antigens / physiology*
  • CTLA-4 Antigen
  • Cell Line
  • Cell Movement / immunology
  • Enzyme Activation
  • Female
  • Humans
  • Immunologic Memory*
  • In Vitro Techniques
  • Integrins / metabolism
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred CBA
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Ovalbumin / immunology
  • Peptide Fragments / immunology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Point Mutation
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / physiology*

Substances

  • Antigens
  • Antigens, CD
  • Antigens, Differentiation
  • CD28 Antigens
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ctla4 protein, mouse
  • Integrins
  • OVA 323-339
  • Peptide Fragments
  • Receptors, Antigen, T-Cell
  • Ovalbumin
  • Phosphatidylinositol 3-Kinases