A ROLE FOR TGF-BETA-1 IN LANGERHANS CELL BIOLOGY - FURTHER CHARACTERIZATION OF THE EPIDERMAL LANGERHANS CELL DEFECT IN TGF-BETA-1 NULL MICE

Previous studies of TGF beta 1 null (-/-) mice indicated that the epid ermis was devoid of Langerhans cells (LC) and that the LC deficiency w as not secondary to the inflammation that is the dominant feature of t he -/- phenotype (Borkowski, T.A., J.J. Letterio, A.G. Farr, and M.C. Udey. 1996. J. Exp. Med. 184:2417-2422). Herein, we demonstrate that d endritic cells could be expanded from the bone marrow of -/- mice and littermate controls. Bone marrow from -/- mice also gave rise to LC af ter transfer into lethally irradiated recipients. Thus, the LC defect in TGF beta 1 null mice does not result from an absolute deficiency in bone marrow precursors, and paracrine TGF beta 1 production is suffic ient for LC development. Several approaches were used to assess the su itability of -/- skin for LC localization. A survey revealed that alth ough a number of cytokine mRNAs were expressed de novo, mRNAs encoding proinflammatory cytokines known to mobilize LC from epidermis (IL-1 a nd TNF alpha) were not strikingly overrepresented in -/- skin. In addi tion, bone marrow-derived LC populated full-thickness TGF beta 1 null skin after engraftment onto BALB/c nu/nu recipients, Finally, the skin of transgenic mice expressing a truncated loricrin promoter-driven do minant-negative TGF beta type II receptor contained normal numbers of LC. Because TGF beta 1 signaling in these mice is disrupted only in ke ratinocytes and the keratinocyte hyperproliferative component of the T GF beta 1 -/- phenotype is reproduced, these results strongly suggest that the LC defect in TGF beta 1 null mice is not due to an epidermal abnormality but reflects a requirement of murine LC (or their precurso rs) for TGF beta 1.