CD8 T cells regulate allergic contact dermatitis by modulating CCR2-dependent TNF/iNOS-expressing Ly6C+ CD11b+ monocytic cells.
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.
Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, Singapore; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore. Electronic address: chong_shu_zhen@immunol.a-star.edu.sg.
Shu Zhen
SZ
Chong
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
Kar Wai
KW
Tan
Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore.
Fiona H S
FHS
Wong
Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore.
Yen Leong
YL
Chua
Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, Singapore.
Yafang
Y
Tang
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
Lai Guan
LG
Ng
Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore.
Veronique
V
Angeli
Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, Singapore.
David M
DM
Kemeny
D000818:Animals; D000950:Antigens, Ly / Q000276:immunology / Q000378:metabolism; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D017449:Dermatitis, Allergic Contact / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000276:immunology* / Q000378:metabolism; D054390:Receptors, CCR2 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism
D000950:Antigens, Ly; D039481:CD11b Antigen; C515335:Ccr2 protein, mouse; C494192:Ly-6C antigen, mouse; D054390:Receptors, CCR2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse