Skin Inflammation During Contact Hypersensitivity Is Mediated by Early Recruitment of CD8+ T Cytotoxic 1 Cells Inducing Keratinocyte Apoptosis

Abstract

Contact hypersensitivity (CHS) is a T cell-mediated, Ag-specific skin inflammation induced by skin exposure to haptens in sensitized individuals. Th1/T cytotoxic 1 cells are effector cells of CHS, whereas Th2/T regulatory CD4+ T cells have down-regulating properties. We have previously shown that CHS to 2,4-dinitrofluorobenzene is mediated by specific CD8+ effector cells, whose cytolytic activity is mandatory for induction of skin inflammation. In this study, using immunohistochemistry and RT-PCR analysis, we show that CD8+ T cells are rapidly recruited into the skin at the site of hapten challenge before the onset of clinical and histological signs of skin inflammation. This early CD8+ T cell recruitment is concomitant with: 1) transient IFN-γ mRNA expression suggesting local activation of effector cells; and 2) induction of keratinocyte (KC) apoptosis which gradually increased to a maximum at the peak of the CHS response. Alternatively, skin infiltration of CD4+ T cells occurred later and coincided with the peak of the CHS reaction and the beginning of the resolution of skin inflammation. Mice deficient in CD8+ T cells did not develop CHS, whereas mice deficient in CD4+ T cells developed an enhanced inflammatory response with increased numbers of CD8+ T cells recruited in the skin associated with massive KC apoptosis. These data show that CHS is due to the early and selective recruitment in the skin of CD8+ T cytotoxic 1 effector cells responsible for KC apoptosis.

Lysophosphatidylcholine is a natural adjuvant that initiates cellular immune responses

“…Upon skin painting, the hapten is taken up by skin DC which migrate to proximal lymph nodes and activate specific T cells. Since the hapten can stay in the skin for a few days in its antigenic form, effector CD8 + T cells are recruited and activated in the dermis and induce CHS through a process involving cytotoxicity and IFNγ synthesis [38,39]. We used suboptimal concentrations of DNFB so that the CHS reaction observed at day 5 was only moderate in intensity and magnitude (Fig.…”

Human CD8+ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

“…Previous studies have shown that CD8 1 T cells are able to infiltrate quickly into inflamed sites [18] that may facilitate their early interaction with DCs. In human psoriasis studies, the administration of alefacept, which reduces infiltration of activated memory CD8 1 T cells, reduced DC content, inflammation and tissue expression of iNOS and IFN-g [19].…”

“…CD8 1 T cells utilize a variety of factors, including IFN-g, GM-CSF, TNF-a and CD40L to activate DCs for the production of 13,14], the key cytokine for Th1 immunity [15]. Importantly, CD8 1 T cells were shown to interact with DCs in both lymph nodes [16] and peripheral tissue sites [4,17] where they exert their pro-Th1 influence.Previous studies have shown that CD8 1 T cells are able to infiltrate quickly into inflamed sites [18] that may facilitate their early interaction with DCs. In human psoriasis studies, the administration of alefacept, which reduces infiltration of activated memory CD8 1 T cells, reduced DC content, inflammation and tissue expression of iNOS and .…”

Skin-Infiltrating CD8+ T Cells Initiate Atopic Dermatitis Lesions

“…For HPRT, CD4, CD8, IFN-␥ the primers have been described elsewhere (19). For IL-4, the sense primer is 5Ј-TCGGCATTTTGAACGAG GTC-3Ј and antisense 5Ј-GAAAAGCCCGAAAGAGTCTC-3Ј.…”