Keratinocyte-associated B7-H1 directly regulates cutaneous effector CD8+ T cell responses

J Immunol. 2010 May 1;184(9):4918-25. doi: 10.4049/jimmunol.0902478. Epub 2010 Apr 2.

Abstract

Keratinocytes (KCs) may play important roles for maintenance of peripheral tolerance in the upper layers of the skin. Coinhibitory signals mediated via the programmed death (PD)-1 and its ligand B7-H1 (PD-L1/CD274) are crucial for the downregulation of T cell immune responses and for the maintenance of peripheral tolerance. In this study, to investigate the role of KC-expressed B7-H1 in the regulation of T cell immune responses, we generated transgenic (tg) mice overexpressing B7-H1 under the control of keratin 14 (K14) promoter (K14-B7-H1 tg). K14-B7-H1 tg mice displayed impaired contact hypersensitivity (CH) responses to primary and secondary hapten challenges. The K14-B7-H1 tg mice did not exhibit substantial impairment of cutaneous dendritic cell migration after sensitization and of hapten-specific proliferation and IFN-gamma production of CD4(+) and CD8(+) T cells in the draining lymph nodes, suggesting that overexpression of B7-H1 on KCs did not affect the induction phase of the CH response. The systemic or s.c. injection of hapten-sensitized T cells into the K14-B7-H1 tg mice did not efficiently induce the CH response. IFN-gamma expression and apoptosis of KCs in the challenged ears were impaired in K14-B7-H1 tg mice. IFN-gamma production by presensitized CD8(+) T cells stimulated with hapten-pulsed KCs was markedly impaired for the KCs obtained from the K14-B7-H1 tg mice but was restored by the addition of an anti-B7-H1 mAb. These results suggest that KC-associated B7-H1 directly downregulates the effector function of CD8(+) T cells by associating with PD-1 at local inflammatory sites and that it plays a role in peripheral T cell tolerance against exogenous Ags.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Apoptosis Regulatory Proteins / genetics
  • B7-1 Antigen / biosynthesis
  • B7-1 Antigen / genetics
  • B7-1 Antigen / physiology*
  • B7-H1 Antigen
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / pathology
  • Cells, Cultured
  • Dermatitis, Contact / immunology
  • Dermatitis, Contact / metabolism
  • Dermatitis, Contact / pathology
  • Down-Regulation / genetics
  • Down-Regulation / immunology
  • Humans
  • Inflammation Mediators / metabolism
  • Inflammation Mediators / physiology
  • Jurkat Cells
  • Keratin-14 / genetics
  • Keratinocytes / immunology*
  • Keratinocytes / metabolism*
  • Keratinocytes / pathology
  • Membrane Glycoproteins / biosynthesis
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Peptides / genetics
  • Peptides / physiology*
  • Programmed Cell Death 1 Receptor
  • Promoter Regions, Genetic / immunology
  • Skin / immunology*
  • Skin / metabolism*
  • Skin / pathology

Substances

  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • B7-1 Antigen
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Inflammation Mediators
  • Keratin-14
  • Membrane Glycoproteins
  • PDCD1 protein, human
  • Peptides
  • Programmed Cell Death 1 Receptor