Blocking 4-1BB/4-1BB ligand interactions prevents herpetic stromal keratitis

J Immunol. 2003 Jul 15;171(2):576-83. doi: 10.4049/jimmunol.171.2.576.

Abstract

Herpetic stromal keratitis (HSK) is a chronic inflammatory process in corneal stroma that results from recurrent HSV type 1 infection. We used the murine model of HSK to demonstrate the importance of the interaction between an inducible T cell costimulatory receptor, 4-1BB, and its ligand, 4-1BB ligand (4-1BBL), in the development of this disease. In BALB/c mice, HSK ordinarily induced by infection with the RE strain of herpes was prevented by blocking 4-1BB/4-1BBL interaction, either by deleting 4-1BB (in mutant 4-1BB(-/-) mice) or by introducing mAbs against 4-1BBL. The majority of T cells infiltrating the infected corneas were 4-1BB(+) activated effector cells that expressed cell surface markers CD44, CD25, and/or CD62L, as well as chemokine receptors CCR1, CCR2, and CCR5, and a limited number of TCR Vbeta chains (Vbeta8.1/8.2, Vbeta8.3, Vbeta10b, and Vbeta5.1/5.2, in order of abundance). Analysis of cell surface phenotypes showed that the failure to develop HSK in the 4-1BB(-/-) mice was associated with a reduced expression of CD62L at the time of T cell migration into the corneal stroma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 4-1BB Ligand
  • Animals
  • Antigens, CD
  • Apoptosis / immunology
  • Cell Movement / immunology
  • Chemokines / biosynthesis
  • Cornea / immunology
  • Cornea / metabolism
  • Cornea / pathology
  • Cytokines / biosynthesis
  • Down-Regulation / genetics
  • Down-Regulation / immunology
  • Gene Deletion
  • Herpesvirus 1, Human / immunology
  • Immunophenotyping
  • Keratitis, Herpetic / metabolism
  • Keratitis, Herpetic / pathology
  • Keratitis, Herpetic / prevention & control*
  • Keratitis, Herpetic / virology
  • L-Selectin / biosynthesis
  • Ligands
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Receptors, Nerve Growth Factor / antagonists & inhibitors*
  • Receptors, Nerve Growth Factor / biosynthesis
  • Receptors, Nerve Growth Factor / deficiency
  • Receptors, Nerve Growth Factor / metabolism*
  • Receptors, Tumor Necrosis Factor / antagonists & inhibitors*
  • Receptors, Tumor Necrosis Factor / biosynthesis
  • Receptors, Tumor Necrosis Factor / deficiency
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Stromal Cells / immunology
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocyte Subsets / virology
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • 4-1BB Ligand
  • Antigens, CD
  • Chemokines
  • Cytokines
  • Ligands
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • TNFRSF9 protein, human
  • TNFSF9 protein, human
  • Tnfrsf9 protein, mouse
  • Tnfsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Necrosis Factor-alpha
  • L-Selectin