Several major points should be emphasized that provide directions for future research. First, using monoclonal reagents we have been able to phenotypically identify four major regions of the human thymus microenvironment: the thymic capsule, interlobular septae and stroma (TE-7+), the subcapsular cortex (TE-4+, Thy-1+, A2B5+, anti-p19+, BB TECS+, TE-3+), the cortex (TE-3+), and the medulla (TE-4+, A2B5+, anti-p19+, BB TECS+). TE-4+ and TE-3+ thymic epithelium constitute HLA+, Ia+ subsets of thymic epithelium that are candidates for cell types of the human thymic microenvironment that might participate in conferring MHC restriction to maturing T lymphocytes. TE-7+ stroma most likely represents the mesodermal-derived thymic component that early in development induces thymic epithelial differentiation. Second, whereas TE-4, anti-p19, and BB TECS antibodies may be thymic epithelial lineage markers, they all react with the basal layer of squamous epithelium of various organs. In particular, in the tonsil, A2B5+, TE-4+ epithelium splays out in the base of tonsillar crypts and morphologically appears similar to thymic medullary epithelial cells. Therefore, these markers of endocrine thymic epithelium may also identify extrathymic areas of T cell differentiation. Third, the concept that thymic epithelium is constantly differentiating in the developed thymus is suggested by the coexpression of TE-4, TE-8, TE-16, and TE-15 antigen by layers of squamous epithelial keratinocytes and by thymic epithelium. That there is a TE-4/TE-8/TE-15 keratinocyte maturation pathway in skin gives credence to the notion that a similar pathway exists from TE-4+, TE-8-, TE-15- endocrine medullary epithelial cells to TE-4-, TE-8+, TE-15+ Hassall's bodies. Fourth, from the literature and the work presented in this review, three phases of thymic microenvironment development can be defined. The first phase is during early fetal development (4 to 8 weeks in humans) when mesodermal-derived fibrous tissue induces endodermal and ectodermal-derived thymic epithelium to proliferate and mature. TE-7+ mesenchymal stroma invaginates TE-4+ thymic epithelium and effects thymic lobulation. The second phase occurs between 9 and 15 weeks fetal development when the thymic primordia is colonized by blood-borne thymocyte precursors. Presumably during this stage, thymic epithelium promotes bone marrow cell colonization of thymus by producing chemoattractant molecules.(ABSTRACT TRUNCATED AT 400 WORDS)