EXAGGERATED AND PERSISTENT CUTANEOUS DELAYED-TYPE HYPERSENSITIVITY INTRANSGENIC MICE WHOSE EPIDERMAL-KERATINOCYTES CONSTITUTIVELY EXPRESS B7-1 ANTIGEN

Since mouse keratinocytes are tolerogenic antigen presenting cells for T cell activation, the expression of second signal molecules such as B7-1 was targeted to epidermal keratinocytes (KC) in vivo in transgeni c mice. The expression vector used to create transgenic mice consisted of a keratin 14 promoter fused 5' to the full length open reading fra me of the cDNA encoding mouse B7-1 (between 10 and 30 copies of the tr ansgene per genome). Expression of B7-1 cell surface protein was asses sed by in situ immunostaining of cryostat sections of tail skin with C TLA-4/Ig fusion protein, revealing high levels of cell surface express ion of B7 by all epidermal KC of transgenic mice, and a lack of such e xpression in nontransgenic animals. The skin of such transgenic mice ( derived from three different founder mice) was grossly and histologica lly normal, with normal numbers of Langerhans cells and dendritic epid ermal T cells. Immunologic challenge of transgenic mice with epicutane ous haptens such as fluorescein isothiocyanate revealed enhanced and p ersistent delayed-type hypersensitivity responses, with an altered kin etics of resolution when compared with nontransgenic controls, These d ata indicate that in normal, nontransgenic mice, tolerogenic antigen p resentation by KC plays an important physiologic role in damping T cel l-mediated inflammation in the skin by competing with professional APC for TCR occupancy in antigen specific T-lymphocytes that migrate into the epidermis. This also implies that altered regulation of B7-1 gene expression by epidermal cells may account for skin ''hyperresponsiven ess'' encountered in some chronic dermatologic disorders.