The invariant chain transports TNF family member CD70 to MHC class II compartments in dendritic cells

Abstract

SummaryCD70 is a TNF-related transmembrane molecule expressed by mature dendritic cells (DCs), which present antigens to T cells via major histocompatibility complex (MHC) molecules. In DCs, CD70 localizes with MHC class II molecules in late endosomal vesicles, known as MHC class II compartments (MIICs). MIICs are transported to the immune synapse when a DC contacts an antigen-specific CD4 + T cell. Consequently, MHC class II and CD70 are simultaneously exposed to the T cell. Thereby, T-cell activation via the antigen receptor and CD70-mediated co-stimulation are synchronized, apparently to optimize the proliferative response. We report here that the invariant chain (Ii), a chaperone known to transport MHC class II to MIICs, performs a similar function for CD70. CD70 was found to travel by default to the plasma membrane, whereas Ii coexpression directed it to late endosomes and/or lysosomes. In cells containing the MHC class II presentation pathway, CD70 localized to MIICs. This localization relied on Ii, since transport of CD70 from the Golgi to MIICs was impeded in Ii-deficient DCs. Biophysical and biochemical studies revealed that CD70 and Ii participate in an MHC-class-II-independent complex. Thus, Ii supports transport of both MHC class II and CD70 to MIICs and thereby coordinates their delivery to CD4 + T cells.

Dual Function of CD70 in Viral Infection: Modulator of Early Cytokine Responses and Activator of Adaptive Responses

“…However, transient blockade of CD70-CD27 interactions was not sufficient to cause changes in Treg numbers or the innate response, which is in agreement with a recent study (29). Since CD70 mediates reverse signaling (37) and translocates together with the invariant chain to the endosomal/lysosomal compartments (38), CD70 may also act by modulating TLR signaling and/or translocation of TLR into endosomal compartment where they interact with microbial ligands.…”

Cross-species association of quail invariant chain with chicken and mouse MHC II molecules

“…Ii is a non-polymorphic type II integral membrane protein (Roche and Cresswell, 1990), located at the cell surface and partially in endosomal/lysosomal compartments (Zwart et al, 2010), which binds MHC class II molecules to form complexes (Ashman and Miller, 1999;Lindner, 2002;Roche, 2011). Our results suggest that the cytosolic and TM domains perform the same localization function in cells (Fig.…”

Targeting the T-Cell Co-stimulatory CD27/CD70 Pathway in Cancer Immunotherapy: Rationale and Potential

“…Newly synthesized CD70 protein travels to late endosomes that also contain MHC class II. Next, CD70 and MHC class II travel to the immunological synapse where they respectively stimulate CD27 and the TCR on the CD4 + T cell [50,51]. CD27 co-stimulation promotes Th1-type effector differentiation of the CD4 + T cell, as found consistently in human and mouse [40,43,52,53] ( Figure 2).…”