Antigen-specific blocking of CD4-specific immunological synapse formation using BPI and current therapies for autoimmune diseases

Abstract

In this review, we discuss T-cell activation, etiology, and the current therapies of autoimmune diseases (i.e., MS, T1D, and RA). T-cells are activated upon interaction with antigen-presenting cells (APC) followed by a "bull's eye"-like formation of the immunological synapse (IS) at the T-cell-APC interface. Although the various disease-modifying therapies developed so far have been shown to modulate the IS and thus help in the management of these diseases, they are also known to present some undesirable side effects. In this study, we describe a novel and selective way to suppress autoimmunity by using a bifunctional peptide inhibitor (BPI). BPI uses an intercellular adhesion molecule-1 (ICAM-1)-binding peptide to target antigenic peptides (e.g., proteolipid peptide, glutamic acid decarboxylase, and type II collagen) to the APC and therefore modulate the immune response. The central hypothesis is that BPI blocks the IS formation by simultaneously binding to major histocompatibility complex-II and ICAM-1 on the APC and selectively alters the activation of T cells from T(H)1 to T(reg) and/or T(H)2 phenotypes, leading to tolerance.

Figure 1

Mechanism of immunological synapse formation during T cell and APC interaction. (A) Initial contact between Signal-1 (TCR/MHC-II-peptide complex) and Signal-2 (LFA-1/ICAM-1complex). (B) Translocation of Signal-1and Signal-2 to form c-SMAC and p-SMAC of the immunological synapse. APC, antigen-presenting cell; SMAC, supramolecular activation clusters; ICAM-1, intercellular adhesion molecule-1; MHC, major histocompatibility complex; TCR, T-cell receptors; LFA, leukocyte function-associated antigen; p-SMAC, peripheral SMAC.

Figure 2

Signaling molecules involved in the interface of T cell and APC interaction. The interaction between T cell and APC involves several pairs of receptors (Signal-1 and -2) and is associated with the release of cytokines (Signal-3). APC, antigen-presenting cell.

Figure 3

The proposed binding of the BPI molecule to MHC-II and ICAM-1, which inhibits the translocation of Signal-1 and Signal-2. ICAM-1, intercellular adhesion molecule-1; MHC, major histocompatibility complex; BPI, bifunctional peptide inhibitor.

Figure 4

The proposed mechanism of activation and suppression of immune response during autoimmune diseases. On the left, interaction between mature/activated DC and naïve T cells is mediated by MHC-II antigen/TCR complex (Signal-1) in the presence of the costimulatory signal (Signal-2) that leads to differentiation intoT_H1 and T_H17 cells. On the right, interaction between immature/steady-state DC and naïve T cells is mediated by MHC-II antigen/TCR complex (Signal-1) in the absence of the costi-mulatory signal (Signal-2) that leads to differentiation intoT_reg cells. T_reg cells produce IL-10 that suppresses the proliferation of T_H1 and T_H17. MHC, major histocompatibility complex; TCR, T-cell receptors; DC, dendritic cells.

Figure 5

Potential mechanism of BPI molecules in altering the differentiation of naïve T cells upon interaction with immature and mature DC. On the right, interaction of steady-state/immature DC with BPI molecule produces differentiation of naïve T cells to IL-10-producingT_reg cells. IL-10 induces the proliferation of immunosuppressant T_H2 cells. On the left, interaction of BPI molecule with mature/activated DC induces immunosuppressant T_H2 cell differentiation. MHC, major histocompatibility complex; TCR, T-cell receptors; DC, dendritic cells; BPI, bifunctional peptide inhibitor.