MHC class II isotype-specific signaling complex on human B cells

Abstract

The highly polymorphic human major histocompatibility complex (HLA) class II molecules are acknowledged as signaling receptors although their coupling to signaling pathways is not yet fully elucidated. In this study, we investigated how HLA class II can be coupled to protein tyrosine kinase (PTK) signaling pathway in B cells and whether there might be differences depending on HLA class II isotype. Using the human B cell line Ramos, we demonstrate that CD19 and CD20 are two HLA class II‐associated receptors that couple HLA class II to PTK signaling pathway where CD20 appears to be amajor component of HLA class II‐mediated activation of Src kinases. Both HLA‐DR and HLA‐DP co‐immunoprecipitate tyrosine‐phosphorylated proteins (p‐Tyr) whereas only activation through HLA‐DR increases the tyrosine phosphorylation of these proteins. Indeed, in contrast to HLA‐DR, cross‐linking HLA‐DP induces neither tyrosine phosphorylation nor homotypic adhesion, and induces ERK1/2 activation. Differential association of these isotypes with CD20 appears to be one of the mechanisms underlying their differential signaling. We provide an experimental evidence for a mechanism by which HLA class II molecules can be coupled to PTK signaling pathway and, underscores their isotypes differential signaling. Further investigation of these mechanisms is likely to provide new insights into how isotype specific MHC class II signaling can contribute to the regulation of the immune response.

Nanomolecular HLA-DR10 Antibody Mimics: A Potent System for Molecular Targeted Therapy and Imaging

“…23 These proteins are also important receptors that have been shown to participate in transmembrane and cytoplasmic signaling. [24][25][26] Although upregulated on the surface membrane of human malignant B-cells, HLA proteins are even more abundant inside these cells (Fig. 8), where they are manufactured and assembled on the endoplasmic reticulum.…”

The Pathway of Antigen Uptake and Processing Dictates MHC Class II-Mediated B Cell Survival and Activation

“…Thus, relevant microdomains containing peptide-MHC have been shown to interact with CD82 and other members of the tetraspan family of integral membrane proteins (38). CII has also been shown to associate with CD19 and CD20, molecules that may couple CII to the protein tyrosine kinase signaling pathway (21). Other molecules have also been reported to be associated with CII, including CD40 (39).…”

“…The different results in our study from those reported before may be due to the binding properties of the different Abs or the type of CII. Indeed, in the mouse study (2), the rate of cell death was related to the type of the Ab used, and different classes of HLA have been found to signal differently following their ligation with anti-HLA Abs (21). Furthermore, in the former study, staining with ethidium bromide has been taken as evidence for B cells undergoing apoptosis in the absence of data showing specific DNA fragmentation.…”

Dynamics of MHC Class II-Activating Signals in Murine Resting B Cells

“…These include B cell activation status (15,16), species differences (8,15), B cell transformation (8), MHC II haplotype or isotype (4,9,17), and signals generated from other cell surface receptors, including the BCR (18) or CD40 (19). Additionally, other factors such as the uptake and processing of Ag may influence the context in which MHC II is found in the plasma membrane and, as a result, dictates the functional outcome of MHC II-mediated signals in B cells.…”