Interaction of HLA‐DR and CD74 at the cell surface of antigen‐presenting cells by single particle image analysis

Abstract

Major histocompatibility complex (MHC) class II-associated antigen presentation involves an array of interacting molecules. CD74, the cell surface isoform of the MHC class II-associated invariant chain, is one such molecule; its role remains poorly defined. To address this, we have employed a high-resolution single-particle imaging method for quantifying the colocalization of CD74 with human leukocyte antigen (HLA)-DR molecules on human fibroblast cells known for their capacity to function as antigen-presenting cells. We have also examined whether the colocalization induces internalization of HLA-DR using HA(307-319), a "universal" peptide that binds specifically to the peptide-binding groove of all HLA-DR molecules, irrespective of their alleles. We have determined that 25 ± 1.3% of CD74 and 17 ± 0.3% of HLA-DR are colocalized, and the association of CD74 with HLA-DR and the internalization of HLA-DR are both inhibited by HA(307-319). A similar inhibition of HLA-DR internalization was observed in freshly isolated monocyte-derived dendritic cells. A key role of CD74 is to translocate HLA-DR molecules to early endosomes for reloading with peptides prior to recycling to the cell surface. We conclude that CD74 regulates the balance of peptide-occupied and peptide-free forms of MHC class II at the cell surface.

Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial

“…In both cases, this included CIITA , the MHC class II transactivator gene and genes encoding for MHC class II HLA molecules ( Fig 7, S4 Table) . Additionally, Regulatory Factor X subunit, RFX5 , which acts in conjunction with CIITA to induce transcription of MHC class II HLA genes, and CD74 , which encodes the MHC class-II-associated Ii (invariant chain) essential for targeting MHC II molecules to the endosomal-lysosomal antigen-processing compartment [45, 46] were found to be differentially expressed in response to SV-AS03 in neutrophils at day 1 ( Fig 7A, S4 Table ). For monocytes, although genes encoding for MHC II proteins were significantly differentially expressed at day 1, the AS03 effect for the MHC II sub-pathway was much less pronounced ( Fig A125 in S2 Text ).…”

Inflammatory Marker Testing Identifies CD74 Expression in Melanoma Tumor Cells, and Its Expression Associates with Favorable Survival for Stage III Melanoma

“…Historically, CD74 was known primarily as the MHC Class II invariant chain, and functions in the molecular processing of MHC II through the Golgi (24). It has a potential role in the anti-tumor immune response (25), and also been shown to be expressed in inflammatory disorders and other inflammation-associated cancers (26).…”

Dynamic range of Nef-mediated evasion of HLA class II-restricted immune responses in early HIV-1 infection

“…Indeed, HLA-DR and Ii modulate antigen presentation [15]. Specifically, increased cell surface expression of Ii can be detrimental to this process as it increases internalization of HLA-DR molecules [30] and interferes with their cellular trafficking [31], thus impairing HLA-II-restricted antigen presentation [16]. Also, higher HLA-DR down-regulation and Ii up-regulation activities in some AP subjects suggests that there are substantial inter-patient differences in Nef's inherent ability to evade HLA class II-mediated immune responses in acute/early infection.…”