Normal thymic cortical epithelial cells developmentally regulate the expression of a B-lineage transformation-associated antigen

Abstract

Nonlymphoid, stromal cells in the mouse thymus are believed to be important in T cell maturation and have been proposed to play a central role in the acquisition of major histocompatibility complex (MHC) restriction and self-tolerance by maturing thymocytes. Both cortical and medullary epithelial cells in the thymus express high levels of class II (A) major histocompatibility antigens (MHC Ags). We show here that a specific subset of these A+ epithelial cells express a transformation-associated antigen (6C3Ag) found previously on the surfaces of Abelson murine leukemia virus-transformed pre-B cells and on those bone marrow-derived stromal cell clones which support normal and preneoplastic pre-B cell proliferation. Among solid lymphoid organs, only the thymus contains 6C3Ag+ cells and within the thymus, this antigen is found exclusively on A+ epithelial cells in cortical regions. It is striking that the expression of the 6C3Ag on thymic epithelium is developmentally regulated, suggesting a role for this lymphostromal antigen in the maturation of the thymic microenvironment.

Early Defect Prethymic in Bone Marrow T Cell Progenitors in Athymicnu/nuMice

“…The development of a functional thymus has been shown to be divided into genetically separable epithelial-mesenchymal and subsequent lympho-stromal interactions (27). Cortical and medullary epithelial cells that respectively support progressive stages of maturation of the developing murine thymocytes have been identified (28,29) and long been known to play critical roles in the development, acquisition of tolerance, MHC restriction, and immune function of these developing T cells (30). Therefore, a likely explanation of the progenitor defect seen in the bone marrow of nu/nu mice is that epithelial cells in the bone marrow microenvironment of nu/nu mice express the abnormal whn gene and fail to deliver a variety of normal differentiation signals to the progenitors, including that which leads to expression of pT␣ on the cell surface.…”

Histidine residue in the zinc-binding motif of aminopeptidase A is critical for enzymatic activity.

“…The BP-1 antigen was identified as a homodimeric, phosphorylated cell surface glycoprotein on pre-B-cells and newly formed B cells in mouse bone marrow (1)(2)(3). This molecule, independently identified as a pre-B-cell neoplasiaassociated antigen and named 6C3 in another laboratory (4), is also expressed on certain bone marrow stromal cell lines and a subpopulation of thymic cortical epithelial cells (5)(6)(7).…”

Molecular cloning of the murine BP-1/6C3 antigen: a member of the zinc-dependent metallopeptidase family.

“…Although expression of the BP-1/6C3 protein has been characterized primarily in hemopoietic and lymphopoietic tissues, it can also be found in nonlymphoid cells, such as the brush border of the small intestine, glomeruli, and proximal renal tubules (ref. 4 (20), (iii) only two of nine cysteine residues are conserved in both molecules (Fig. 3), and (iv) the BP-1/6C3 molecule is not expressed on mouse myeloid cells (1-3).…”

“…The subunits of the BP-1/6C3 antigen have a protein backbone of 110 kDa, but differentially glycosylated forms of this antigen may be expressed by different cell types (3-5). The molecule expressed on early B-lineage cells is a 140-kDa homodimer, whereas lymphogenic bone marrow-derived stromal cell lines express a 135-kDa homodimer, and a subpopulation of thymic cortical epithelial cells may express a 130-kDa homodimeric form of this molecule (1,4,5).Several observations suggest that the BP-1/6C3 molecule may play an important role in regulating growth and differentiation of early B-lineage cells: (i) expression is limited to early stages of B-lineage differentiation (1, 3); (ii) interleukin 7, a bone marrow stromal cell cytokine, induces both proliferation and expression of the BP-1/6C3 antigen by marrowderived precursors (6); (iii) expression of this antigen on bone marrow-derived stromal cell lines correlates with their ability to support pre-B cell growth (5); (iv) neoplastic pre-B cells typically express high levels of the antigen (3, 7, 8); and (v) the BP-1/6C3 antigen is a phosphoprotein, as are a number of other cell surface molecules that may influence cell activation (3, 9-11).To explore further the nature and functional role of this molecule, we have purified it, obtained partial sequences of random peptides, and used them to identify cDNA clones encoding the BP-1/6C3 antigen. The predicted amino acid sequence** suggests that this protein is a member of the zinc-dependent metallopeptidase family (12).…”

“…The BP-1/6C3 molecule is expressed on early B-lineage cells in hemopoietic tissues but is not found on mature lymphocytes in peripheral lymphoid tissues. The subunits of the BP-1/6C3 antigen have a protein backbone of 110 kDa, but differentially glycosylated forms of this antigen may be expressed by different cell types (3)(4)(5). The molecule expressed on early B-lineage cells is a 140-kDa homodimer, whereas lymphogenic bone marrow-derived stromal cell lines express a 135-kDa homodimer, and a subpopulation of thymic cortical epithelial cells may express a 130-kDa homodimeric form of this molecule (1,4,5).…”