A Secreted Form of the Major Histocompatibility Complex Class II-associated Invariant Chain Inhibiting T Cell Activation

Major histocompatibility complex (MHC) class II molecules function at the cell surface to present antigenic peptides to T helper cells. Intracellularly, MHC class II molecules are associated with the invariant chain (Ii). Ii can modulate MHC class II-dependent T cell activation through (i) assistance in the export of MHC class II molecules from the endoplasmic reticulum, (ii) providing a targeting signal for endosomal/lysosomal compartments, and (iii) preventing peptides from associating prematurely with MHC class II molecules. Here we describe the generation and subsequent secretion of a lumenal form of Ii, IiP25. IiP25 lacked the targeting sequences for transport to MHC class II compartments but contained part of the CLIP region that is known to compete with antigenic peptides for binding to MHC class II molecules. When added to an antigenic peptide presentation model system, IiP25 inhibited T cell activation by competing for the CLIP binding site at the plasma membrane. Secretion of a lumenal Ii fragment may represent an additional mechanism to modulate T cell activation by MHC class II molecules.