One of the essential functions of dendritic cells is to take up Ags in peripheral tissues and migrate into secondary lymphoid organs to present Ags to lymphocytes for the induction of immune responses. Although many studies have demonstrated that the migration of dendritic cells is closely associated with the development of immune responses, little is known about factors that inhibit dendritic cell migration and control the extent of immune responses to Ag stimulation. We show that Slit2, a neuronal repellent factor, is up-regulated in the skin by allergen sensitization and down-regulates the migration of Langerhans cells. The effect is mediated by direct interaction of Slit2 with cells that express a Slit-specific receptor, Robo1. Slit2-mediated inhibition of Langerhans cell migration results in suppression of contact hypersensitivity responses. These findings provide insights into a novel mechanism by which Slit2 functions as an anti-inflammatory factor for the initiation of immune responses.

ICAM‐1 (CD54) plays an important role in the cell‐cell interaction and migration of leukocytes. Previous studies have shown that ICAM‐1 is involved in inflammatory reactions and that a defect in ICAM‐1 gene inhibits allergic contact hypersensitivity. This study indicates that the migration of hapten presenting Langerhans cells into the regional lymph nodes was significantly reduced in ICAM‐1‐deficient mice compared to wild‐type C57BL/6 mice. The reduced number of dendritic cells in regional lymph nodes did not result from abnormal migration of Langerhans cells into the skin of ICAM‐1‐deficient mice. The concentration and distribution of Langerhans cells in the naïve skin of ICAM‐1‐deficient mice was equal to that of wild‐type mice. Following hapten sensitization, Langerhanscell migration out of the skin and recruitment of fresh Langerhans cells back to the epidermis was not affected in ICAM‐1‐deficient mice. Further experiments demonstrated that ICAM‐1 deficiency on lymphatic endothelium rather than on dendritic cells was responsible for the reduced migration of Langerhans cells into draining lymph nodes. This study indicates that ICAM‐1 regulates the migration of dendritic cells into regional lymph nodes but not into or out of the skin.

It has been reported that gammadeltaT cells are required for transfer of contact hypersensitivity responses by hapten-primed T cells. The mechanism by which they do so, however, remains to be elucidated. To specifically investigate the role of gammadeltaT cells in the development of contact hypersensitivity, this study employed Tdelta gene knockout mice that are deficient in gammadeltaT cells but are normal in the development of alphabetaT cells. The result indicates that contact hypersensitivity responses were significantly greater in gammadeltaT cell deficient mice than in wild-type mice. Similar results were obtained when wild-type mice were depleted of gammadeltaT cells with antibody treatment before hapten sensitization. Depletion of CD4+ T cells did not affect the increased contact hypersensitivity response in gammadeltaT cell deficient mice, suggesting that the effect of gammadeltaT cells is on CD8+ T cells and does not require CD4+ T cells. Further experiments demonstrated that primed CD8+ T cells from the deficient mice exhibited significantly higher CTL activity. The cytokine profile of CD4+ T cells was not significantly altered. Transfer of primed lymph node cells from hapten-primed gammadeltaT cell deficient mice elicited a similar level of contact hypersensitivity in naive wild-type and the deficient recipient mice, indicating that gammadeltaT cells have little effect on the elicitation of primed T cells and contact hypersensitivity responses. We conclude that gammadeltaT cells downregulate contact hypersensitivity responses to hapten sensitization by limiting the development of hapten-specific CD8+ effector T cells during sensitization and that this effect is independent of CD4+ T cells.

A body of evidence indicates that expression of the programmed cell death 1 (PD-1) receptor by activated T cells plays an important role in the down-regulation of immune responses; however, the functions of its known ligands, B7-H1 (PD-L1) and B7-dendritic cell (DC; PD-L2), at the effector phase of immune responses are less clear. In the current study, we investigated the roles of B7-H1 in DC-mediated regulation of hapten-activated T cells and the delayed-type contact hypersensitivity response in primed animals. We found that the expression of B7-H1 and B7-DC was induced on activation of DC by hapten stimulation. Blockade of B7-H1, but not B7-DC, enhanced the activity of hapten-specific T cells. Interaction with a DC line that expresses high cell-surface levels of B7-H1 (B7-H1/DC) suppressed the proliferation of, and cytokine production by, activated T cells. In vivo administration of hapten-carrying B7-H1/DC desensitized the response of sensitized animals to hapten challenge, and this desensitization was hapten-specific. These data indicate that B7-H1 expressed by DC mediates inhibitory signals for activated T cells and suppresses the elicitation of immune responses. The ability of B7-H1/DC to inhibit the function of preactivated T cells in vivo suggests novel strategies for the treatment of immune response-mediated disorders.