Antagonistic roles of CD4+ and CD8+ T-cells in 7,12-dimethylbenz(a)anthracene cutaneous carcinogenesis.
The role that cell-mediated immune responses play during cutaneous carcinogenesis has received little attention. In this study, we evaluated the contribution of CD4(+) and CD8(+) T cells in C3H/HeN mice that were subjected to a two-stage 7,12-dimethylbenz(a)anthracene (DMBA) initiation, 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion skin carcinogenesis protocol. In CD8 knockout (CD8(-/-)) mice, allergic contact hypersensitivity to DMBA was reduced compared with wild-type (WT) C3H/HeN mice. On the other hand, CD4 knockout (CD4(-/-)) mice developed an exaggerated contact hypersensitivity response. CD4(+) T cells from DMBA contact-sensitized mice preferentially produced interleukin 4 (IL-4), IL-10, and IL-17; CD8(+) T cells, on the other hand, secreted IFN-gamma. When CD4(-/-), CD8(-/-), and WT mice were subjected to a standard two-stage DMBA/TPA cutaneous carcinogenesis protocol, the percentage of mice with tumors was much greater (P < 0.001) in CD8(-/-) mice than in WT mice. In contrast, the percentage of tumors was significantly less (P < 0.001) in CD4(-/-) mice than in WT mice. Similar results were obtained when the data were evaluated as the number of tumors per mouse. These findings indicate that (a) CD8(+) T cells are the predominant effector cells in allergic contact hypersensitivity to DMBA and that CD4(+) T cells have an inhibitory role and (b) the development of CD8(+) T cells plays a protective role in skin tumor development whereas CD4(+) T cells have the opposite effect. Manipulation of T-cell subpopulations that are induced by carcinogenic chemicals, like DMBA, could be a means of preventing skin cancers caused by these agents.
Yusuf
Nabiha
N
Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham and Birmingham VA Medical Center, Birmingham, Alabama, USA. nabiha@uab.edu
Nasti
Tahseen H
TH
Katiyar
Santosh K
SK
Jacobs
Michael K
MK
Seibert
Megan D
MD
Ginsburg
Alexis C
AC
Timares
Laura
L
Xu
Hui
H
Elmets
Craig A
CA
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002273:Carcinogens; D003713:Dendritic Cells / Q000378:metabolism; D003877:Dermatitis, Contact; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012878:Skin Neoplasms / Q000139:chemically induced / Q000517:prevention & control
D002273:Carcinogens; D015127:9,10-Dimethyl-1,2-benzanthracene; D007371:Interferon-gamma