A novel regulatory pathway for autoimmune disease: Binding of partial MHC class II constructs to monocytes reduces CD74 expression and induces both specific and bystander T-cell tolerance

Abstract

Treatment with partial (p)MHC class II-β1α1 constructs (also referred to as recombinant T-cell receptor ligands – RTL) linked to antigenic peptides can induce T-cell tolerance, inhibit recruitment of inflammatory cells and reverse autoimmune diseases. Here we demonstrate a novel regulatory pathway that involves RTL binding to CD11b+ mononuclear cells through a receptor comprised of MHC class II invariant chain (CD74), cell-surface histones and MHC class II itself for treatment of experimental autoimmune encephalomyelitis (EAE). Binding of RTL constructs with CD74 involved a previously unrecognized MHC class II-α1/CD74 interaction that inhibited CD74 expression, blocked activity of its ligand, macrophage migration inhibitory factor, and reduced EAE severity. These findings implicate binding of RTL constructs to CD74 as a key step in both antigen-driven and bystander T-cell tolerance important in treatment of inflammatory diseases.

The use of flow cytometry to assess a novel drug efficacy in multiple sclerosis

“…The use of flow cytometry based assays enabled us to identify the predominant cell population that bind these constructs and to follow the changes in the partial MHC class II native cell surface receptor, the class II invariant chain (CD74), during the course of EAE and correlate the treatment response with this potential disease biomarker (Benedek et al 2013). We further identified the DRα1 domain, but not the DR2β1 domain as the RTL component that binds and down-regulates CD74 (Meza-Romero et al 2014; Vandenbark et al 2013). …”

“…These constructs could interact directly with the cognate TCR and act as partial TCR agonists and trigger suboptimal downstream signaling, cytokine shift and loss of encephalitogenic response (Burrows et al 2001; Sinha et al 2009). RTL treatment of EAE was established previously in different models of the disease including DR*1501-Tg mice that develop EAE only after injection of mouse (m)MOG-35–55 peptide (Vandenbark et al 2003), DR*1502-Tg mice that develop EAE after injection of human (h)MOG-35–55 peptide (Sinha et al 2010b), MBP-TCR/DR2-Tg mice that develop EAE after injection of MBP-85–99 peptide (Vandenbark et al 2013), C57BL/6 WT mice that develop EAE after injection of mouse (m)MOG-35–55 peptide and SJL/J mice that develop EAE after injection of PLP-139–151 peptide (Huan et al 2004; Sinha et al 2007). Recently, we developed DRα1 constructs that are covalently tethered to different myelin peptides.…”

Taming the TCR: Antigen-Specific Immunotherapeutic Agents for Autoimmune Diseases

“…However, as site-directed mutation of the external face of the RTL to prevent aggregation does not diminish their biological effects, it is not clear whether they affect T cell activation through this mechanism alone [78]. RTLs were found to bind in an antigen-independent manner to a ligand present on CD19 + B cells, CD11b + macrophages/dendritic cells, and CD11c + dendritic cells [79]; this ligand has been identified as the invariant chain (CD74) [80]. T cell proliferation induced by incubation with free antigen and CD11b + macrophages was suppressed by the presence of RTL; in contrast, RTLs could not suppress T cell proliferation in response to CD19 + APCs [79].…”

Stem Cell Therapy in Autoimmune Rheumatic Diseases: a Comprehensive Review

“…The mechanisms of immune tolerance is based on a complex system of interactive elements, including certain cell types ranging from Treg cells [36], macrophages, B cells, and their respective cytokines and signaling pathways [5,[37][38][39][40]. HSC transplantation takes advantage of its ability to reset the immune system to be skewed toward tolerance vs autoreactivity.…”

“…The etiology of ARD is unknown. Dysregulation of innate and adaptive immunity [2], breaking of tolerance [3][4][5], production of autoantibodies [6][7][8][9], and generation of autoreactive T and B cells [10][11][12], lead to necrosis, scaring, and organ dysfunction and account for many of the clinical manifestations of ARD [13,14]. Due to the complexity of the pathogenesis, there is no universal therapeutic approach that is effective for all cases of ARD.…”