Novel Immune Check-Point Regulators in Tolerance Maintenance

Abstract

The great success of anti-cytotoxic lymphocyte antigen 4 (CTLA4) and anti-programed cell death protein 1 (PD1) in cancer treatment has encouraged more effort in harnessing the immune response through immunomodulatory molecules in various diseases. The immunoglobulin (Ig) super family comprises the majority of immunomodulatory molecules. Discovery of novel Ig super family members has brought novel insights into the function of different immune cells in tolerance maintenance. In this review, we discuss the function of newly identified B7 family molecules, B7-H4 and V-domain Ig Suppressor of T cell Activation (VISTA), and the butyrophilin/butyrophilin-like family members. We discuss the current stages of immunomodulatory molecules in clinical trials of organ transplantation. The potential of engaging the novel Ig superfamily members in tolerance maintenance is also discussed. We conclude with the challenges remaining to manipulate these molecules in the immune response.

Keywords: B7; butyrophilin; immune tolerance.

Figure 1

B7-H4 is a co-inhibitory molecule on APC (blue) and interacts with its unknown receptor (receptor X) on T cells (green) to deliver negative signaling during T cell activation. Left: in the presence of B7-H4-receptor X interaction, T cells proliferate at a lower rate and produce lower amount of IL2 (purple), lower IFNγ (black), and higher IL17 (red). Middle: antagonistic anti-B7-H4 (magenta triangle) blocks the interaction between B7-H4 and receptor X. T cells proliferate at a higher rate and produce more IL2. Right: B7-H4 overexpression leads to lower T cell proliferation, lower IL2 and IL17 production, and higher IFNγ production.

Figure 2

VISTA is a co-inhibitory molecule on both APC (blue) and T cells (green). VISTA is expressed on APC and interacts with the partner (receptor X) on T cells. VISTA can also be a co-inhibitory receptor on T cells and binds to its unknown ligand (ligand Y) on APC. Both interactions deliver negative signaling to T cell activation.