CD8 T cells regulate allergic contact dermatitis by modulating CCR2-dependent TNF/iNOS-expressing Ly6C+ CD11b+ monocytic cells

J Invest Dermatol. 2014 Mar;134(3):666-676. doi: 10.1038/jid.2013.403. Epub 2013 Sep 23.

Abstract

Monocytes and their derived cells have critical roles in inflammation and immune defense. However, their function in skin diseases such as allergic contact dermatitis remains poorly defined. Using a model of contact hypersensitivity (CHS) toward 2,4-dinitrochlorobenzene, we show that Ly6C+ CD11b+ monocytic cells participate in the pathophysiology of CHS and their accumulation is regulated by effector CD8 T cells. These Ly6C+ CD11b+ monocytic cells are the primary contributors of tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) and derive from Ly6C(hi)CCR2+ monocytes, as they were absent in non-inflamed skin and accumulate as a consequence of inflammation in a C-C chemokine receptor type 2 (CCR2)-dependent manner. Importantly, CCR2(-/-) mice, or wild-type mice depleted of monocytes via clodronate liposomes, display a marked decrease in TNF-α and iNOS expression accompanied by attenuated skin inflammation. Using transgenic mice and antibody depletion, we show that effector CD8 T cells regulate the accumulation of Ly6C+ CD11b+ monocytic cells through IL-17 and activate them for TNF-α and iNOS through IFN-γ. CD8 T cell-derived IFN-γ was also critical for the accumulation of the major histocompatibility complex II-expressing Ly6C+ CD11b+ subset, which expressed intermediate levels of CD11c and costimulatory molecules. Taken together, our findings provide further insight into the pathophysiology of allergic contact dermatitis by showing that CD8 T cells regulate the inflammatory cascade through TNF/iNOS-expressing Ly6C+ CD11b+ monocytic cells.

Publication types

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

MeSH terms

  • Animals
  • Antigens, Ly / immunology
  • Antigens, Ly / metabolism
  • CD11b Antigen / immunology
  • CD11b Antigen / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Dermatitis, Allergic Contact / immunology*
  • Dermatitis, Allergic Contact / metabolism
  • Female
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Nitric Oxide Synthase Type II / immunology*
  • Nitric Oxide Synthase Type II / metabolism
  • Receptors, CCR2 / immunology*
  • Receptors, CCR2 / metabolism
  • Signal Transduction / immunology
  • Tumor Necrosis Factor-alpha / immunology*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antigens, Ly
  • CD11b Antigen
  • Ccr2 protein, mouse
  • Ly-6C antigen, mouse
  • Receptors, CCR2
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse