Carcinogen-modified dendritic cells induce immunosuppression by incomplete T-cell activation resulting from impaired antigen uptake and reduced CD86 expression.
Exposure of the skin to environmental stimuli, such as chemical or physical carcinogens, modifies the local skin environment, including depletion of epidermal Langerhans' cells (LC). Any subsequent exposure of the LC-depleted skin to antigen results in the generation of antigen-specific tolerance. In this study we evaluated the antigen-bearing cells in the draining lymph nodes by capitalizing on the fluorescent nature of the contact sensitizer, fluorescein isothiocyanate (FITC). When FITC was applied to the skin of normal mice, two distinct populations of antigen-bearing cells were identified in the draining lymph nodes. They were classified as either FITChi or FITClo on the basis of their fluorescence intensity and thus the amount of antigen they internalized. Only FITClo cells were detected in the lymph nodes draining FITC-treated murine skin that had been depleted of epidermal LC by prior treatment with the complete carcinogen 9,10-dimethyl 1,2-benzanthracene (DMBA). Functional analysis of these cells revealed that the FITChi cells, but not the FITClo cells, induced antigen-specific T-cell proliferation. Further analysis of the FITClo cells from the DMBA-treated mice demonstrated that these cells had reduced levels of CD80 expression, had substantially reduced levels of CD86 expression and performed poorly as co-stimulator cells in an anti-CD3-mediated proliferative assay. Nonetheless these cells still induced early signs of T-cell activation and interleukin-12 production. Consequently the FITClo cells migrating from the LC-depleted skin, through a combination of reduced antigen presentation and reduced co-stimulatory activity, induced a state of unresponsiveness or anergy in the responder T cells in a similar manner to that observed when antigen presentation occurs in the absence of co-stimulation. We propose that these unresponsive, or anergic cells, account for the antigen-specific tolerance observed in these experiments.
Woods
G M
GM
Division of Pathology, University of Tasmania, Hobart, Australia.
Doherty
K V
KV
Malley
R C
RC
Rist
M J
MJ
Muller
H K
HK
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology*; D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen; D017252:CD3 Complex / Q000276:immunology; D060908:CTLA-4 Antigen; D002273:Carcinogens / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000494:pharmacology; D007108:Immune Tolerance; D018796:Immunoconjugates; D018664:Interleukin-12 / Q000032:analysis / Q000276:immunology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D017252:CD3 Complex; D060908:CTLA-4 Antigen; D002273:Carcinogens; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D005456:Fluorescent Dyes; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D018664:Interleukin-12; D015127:9,10-Dimethyl-1,2-benzanthracene; D000069594:Abatacept; D016650:Fluorescein-5-isothiocyanate