The interaction between helper T cells and B cells, leading to the production of antibody to thymus-dependent antigens, was the first cell interaction clearly defined in the immune system; it remains both paradigmatic and controversial. Two requirements of this interaction, that the helper cell (TH) and the B cell must recognize antigenic determinants that are physically linked, and that the TH and the B cell must share genes encoding major histocompatibility complex (MHC) class II molecules, led to the concept that TH-B interaction required an intimate physical association of the two cell types. But in vitro studies have shown that TH can be replaced by soluble, antigen-nonspecific factors, capable of activating any B cell to secrete antibody. We have previously proposed that the requirements for TH-B contact might result from TH cells releasing their lymphokines in a polar fashion directed at that portion of the cell membrane where T-cell receptor cross-linking is actually occurring. Using an artificial monolayer of a cloned helper T-cell line, we show that lymphokines are released preferentially over the area of receptor cross-linking under conditions of limited TH-cell activation. Thus, it appears that one important aspect of the specificity of TH-B cell interactions is the receptor-directed polar release of helper lymphokines.
Branching patterns and regulatory networks differ between branched organs. It has remained unclear whether a common regulatory mechanism exists and how organ-specific patterns can emerge. Of all previously proposed signalling-based mechanisms, only a ligand-receptor-based Turing mechanism based on FGF10 and SHH quantitatively recapitulates the lung branching patterns. We now show that a GDNF-dependent ligand-receptor-based Turing mechanism quantitatively recapitulates branching of cultured wildtype and mutant ureteric buds, and achieves similar branching patterns when directing domain outgrowth in silico. We further predict and confirm experimentally that the kidney-specific positive feedback between WNT11 and GDNF permits the dense packing of ureteric tips. We conclude that the ligand-receptor based Turing mechanism presents a common regulatory mechanism for lungs and kidneys, despite the differences in the molecular implementation. Given its flexibility and robustness, we expect that the ligand-receptor-based Turing mechanism constitutes a likely general mechanism to guide branching morphogenesis and other symmetry breaks during organogenesis.
A common developmental process, called branching morphogenesis, generates the epithelial trees in a variety of organs, including the lungs, kidneys, and glands. How branching morphogenesis can create epithelial architectures of very different shapes and functions remains elusive. In this review, we compare branching morphogenesis and its regulation in lungs and kidneys and discuss the role of signaling pathways, the mesenchyme, the extracellular matrix, and the cytoskeleton as potential organ-specific determinants of branch position, orientation, and shape. Identifying the determinants of branch and organ shape and their adaptation in different organs may reveal how a highly conserved developmental process can be adapted to different structural and functional frameworks and should provide important insights into epithelial morphogenesis and developmental disorders.
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