Localization and Intracellular Transport of MHC Class II Molecules in Bone Marrow-Derived Dendritic Cells

Abstract

Expression of class II molecules is restricted to certain cell types, including B lymphocytes, dendritic cells (DC) from various tissues (e.g. Langerhans cells from skin) and macrophages. Dendritic cells are a system of potent antigen presenting cells (APC) that are characterized by their strong capacity to stimulate immunologically naive T cells^1,2. A key function of DC is thought to be the acquisition of antigens in peripheral tissues and their transport to draining lymph nodes for presentation of the processed peptides to the T lymphocytes. Until recently, the major limitation to study the cell biology of dendritic cells has been the absence of long term cell lines and clones. However, the finding that granulocyte-macrophage colony stimulating factor (GM-CSF)³ promotes growth and maturation of large quantities of DC issued from bone marrow progenitors⁴ provided us with a tool to study the MHC class II transport and distribution in these important APCs. Antigens must be converted in short peptides and loaded on the major histocompatibility complex (MHC) molecules before they can trigger an immune response⁵. Class II associated peptides are derived from extracellular proteins or endogenous proteins that have access to the endocytic pathway. Class II molecules associate with the Invariant chain (Ii) in the endoplasmic reticulum (ER)⁶ and are targeted to the endocytic pathway. Class II molecules accumulate transiently in endocytic compartments designated MHC class II compartment (MIIC)^7,8,9 or class II vesicles (CIIV)^10,11. CIIV are physically and biochemically distinct from endosomes and lysosomes but do, however, contain early endocytic markers such as transferrin receptor and surface immunoglobulins. MIIC, on the other hand, are depleted of recycling receptors and are enriched in late endocytic markers such as Lamp 1. Bone marrow derived DC were cultivated in presence of GM-CSF and a cell biological analysis was performed at different periods of their development. we have shown that major changes in the distribution of class II molecules can be observed during the maturation of DC. Additionaly, we have characterized a new population of DC, representing an intermediate stage of maturation in which CIIV and MIIC can coexist. This developmental switch is coordinated with changes in the distribution of the invariant chain, as well as a dramatic acceleration of class II transport to the plasma membrane.