Hapten skin sensitization induces development of TLR4-dependent inflammatory monocytes that are required for elicitation of skin contact hypersensitivity responses αααα

Abstract

Abstract Contact hypersensitivity (CHS) to skin sensitization and challenge with haptens is mediated by hapten-primed CD8 T cell populations producing IFN-γ and IL-17. Following hapten challenge these primed CD8 T cells induce hapten-presenting endothelial cells (EC) to produce CXCL1/CXCL2 directing the recruitment and activation of a population of inflammatory monocytes (IM) expressing Gr-1, Ly6C, CXCR2, CD11c, FasL and perforin that are required for hapten-primed CD8 T cell infiltration into the parenchymal skin tissue to mediate CHS. This study investigated mechanisms promoting development of these IM. The IM were absent in the bone marrow of hapten sensitized mice with defective IL-1, TNFα or TLR4 receptor signaling. Sensitized TLR4−/− mice lacked CHS responses to challenge despite equivalent numbers of hapten primed CD8 T cells producing IFNγ and IL-17 in skin-draining lymph nodes as sensitized wild type (WT) mice. IM infiltration into hapten challenged skin of sensitized TLR4−/− was absent at 6 hrs. post-challenge and was accompanied by absent skin mRNA expression of CXCL1, CXCL2, IFNγ, GCSF, TNFα, and CCL20. Whereas hapten primed CD8 T cells from sensitized TLR4−/− mice transferred CHS responses to challenged naïve WT mice, transfer of hapten-primed WT CD8 T cells to naïve TLR4−/− mice failed to elicit CHS responses. IM isolated from the bone marrow of sensitized WT mice and transferred at hapten challenge to sensitized TLR4−/− mice restored the absent CHS response and challenged skin expression of CXCL2, IFNγ, and G-CSF mRNA. These results indicate that TLR4 signaling is required for the bone marrow development of IM that are critical for hapten-primed CD8 T cell infiltration into challenged skin during elicitation of CHS responses.