Swetman, Claire Alexandra; (2002) Molecular Mechanisms of Dendritic Cell Dendrite Formation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The morphology of antigen presenting dendritic cells (DC) is characterised by the possession of numerous long arborising processes known as dendrites. The formation of these processes by DC, both in the periphery and in lymphoid organs, is believed to contribute to the remarkable efficiency with which they take up, process and present antigen to T cells. However, the process of dendrite formation and the signalling pathways that lead to the formation of these dendrites remain obscure. This study describes an in vitro model in which human immature DC, but not LPS-matured DC, form long processes, similar to those formed in vivo, upon attachment to the extracellular matrix (ECM) component fibronectin (FN). The formation of these processes was found to be β1 integrin-dependent and involved initial attachment of a cell protrusion to the FN substrate and subsequent movement of the cell body away from the adhesion site, to leave behind a long slender dendrite. Immunofluorescence studies revealed that DC dendrites were composed of actin and tubulin and that inhibition of these proteins resulted in a failure of DC to form dendrites. Furthermore, dendrite formation, but not their maintenance, was found to be dependent on the activity of Rho GTPases. More specifically, Cdc42 and Rac1 were both required for the migration step of process formation, promoting cell spreading and extension. In contrast, RhoA, and its downstream effector p160ROCK, regulated the release of adhesions to the substratum, and associated cellular contraction. Consequently, inhibition of RhoA/p160ROCK leads to the formation of longer dendrites. DC therefore co-ordinate adhesion and protrusion to perform a specialised process of cellular morphogenesis, which differentiates these cells from all other cells of the immune system and may contribute to their distinctive function.

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