DEFICIENT ANTIGEN PRESENTATION BY LANGERHANS CELLS FROM ATHYMIC (NU NU) MICE - RESTORATION WITH THYMIC TRANSPLANTATION OR ADMINISTRATION OFCYTOKINES/

Epidermal Langerhans cells (LC) are a unique subtype of I-A+ dendritic cells able to present Ag for CD4-dependent immune responses. To inves tigate whether cutaneous Ag presentation is regulated by thymic elemen ts or soluble factors produced by thymus-derived cells, we compared LC function in athymic nude mice and euthymic normal controls. Examinati on of the ability of LC to present alloantigens to T cell-enriched res ponder populations, and insulin to an insulin-specific T cell hybridom a, demonstrated that this function is deficient in LC from inbred and outbred strains of congenitally athymic (nu/nu) mice compared with eut hymic litter mates. Adoptive transfer of thymic tissue from euthymic t o athymic mice reconstituted the ability of LC derived from athymic mi ce to present alloantigens. To investigate whether an altered local cy tokine microenvironment was responsible for the diminished LC function in athymic mice, various cytokines were administered in vivo and in v itro before determination of alloantigen presentation by epidermal cel ls from athymic and euthymic mice. Continuous intraperitoneal infusion of granulocyte-macrophage colony stimulating factor (GM-CSF) or TNF-a lpha, but not IL-1alpha or IL-2, restored alloantigen presenting abili ty in athymic LC. In vitro preincubation of LC in GM-CSF or TNF-alpha but not in other cytokines tested also reconstituted alloantigen prese ntation by LC from athymic mice in most, but not all, of the experimen ts performed. Furthermore, analysis of cytokine production by epiderma l cells in athymic and euthymic mice revealed that epidermal cells fro m athymic mice produce less GM-CSF and more TNF-alpha, but normal amou nts of various other cytokines. However, reconstitution of athymic mic e with thymic tissue did not result in normalization of GM-CSF or TNF- alpha production by epidermal cells. These data suggest that LC Ag pre senting ability is regulated by thymic factors and that adequate funct ion of cutaneous APC in situ may require the continuous presence of su fficient amounts of cytokines including GM-CSF and TNF-alpha.