Systemic Treatment with Anti-CD40 Antibody Stimulates Langerhans Cell Migration from the Skin

Epidermal Langerhans cells (LCs) play a pivotal role in the initiation of cutaneous immune responses. The maturation of LCs and their migration from the skin to the T cell areas of draining lymph nodes are essential for the delivery and presentation of antigen to naïve T cells. CD40, which acts as a costimulatory molecule, is present on LCs and the basal layer of keratinocytes in the skin. We show here that systemic treatment of mice with anti-CD40 antibody stimulates the migration of LCs out of the epidermis with a 70% reduction in LC numbers after 7 days, although changes in LC morphology are detectable as early as day 3. LC numbers in the epidermis returned to 90% of normal by day 21. As well as morphological changes, LC showed up-regulated levels of Class II and ICAM-1, with only minimal changes in CD86 expression 3 days following anti-CD40 treatment. Despite increased levels of Class II and ICAM-1, epidermal LC isolated from anti-CD40 treated mice were poor stimulators of a unidirectional allogeneic mixed leucocyte reaction (MLR), as were epidermal LC isolated from control mice. These results indicate that CD40 stimulation is an effective signal for LC migration, distinct from maturation of immunostimulatory function in the epidermis, which is not altered. These observations may have important implications for the mechanism of action of agonistic anti-CD40 antibodies, which have been used as an adjuvant in models of infection and experimental tumours and the primary immunodeficiency Hyper IgM syndrome caused by deficiency of CD40 ligand.