Fc γ Receptor III

Introduction to Fc γ Receptor III

Fc receptors (FcRs) are membrane molecules named for their specific binding for the Fc region of the antibody. Majorly distributed on the surface of B lymphocytes, dendritic cells, natural killer cells, neutrophils, etc. FcRs bind to antibodies that are attached to infected cells or invading pathogens and exert protective functions to the immune system through antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity (ADCC).

According to the binding antibody subtype (or heavy chain), FcRs are generally divided into several different types, among which Fc-gamma receptors (FcγRs) are those who bind to the most common class of antibody IgG. FcγRs are further divided into FcγR I, FcγR II, and FcγR III based on the difference in their structures and antibody affinities. FcγR III (CD16) is an activating receptor with a low affinity that is mainly found on the natural killer cells, monocytes, and macrophages, signaling and inducing the cytokine release, microbe killing, and powerful ADCC function. In recent years, FcγR III-mediated ADCC has made great achievements in drug discovery and immunotherapy.

Fig.1 Diversity of FcγR-mediated antiviral effector functions. (Bournazos, 2020)

γδ T Cell Fc γ Receptor III

Human γδ T cells are a subpopulation of T lymphocytes representing 1%~5% of peripheral blood T cells, which are characterized by the distinctive T-cell receptor (TCR) consisting of a γ and δ chain. Despite circulating in a minor group, these featured γδ T cells play a considerable role in both initial and adaptive immune responses.

As a critical cytotoxic subgroup, γδ T cells express a wide spectrum of receptors binding to antigens and inducing a variety of effector functions. In addition to featured γδ-TCR and several important natural killer receptors (NKRs), γδ T cells are the major effector T cell carrying FcγR III, a low-affinity receptor primarily found on the natural cells. It has been indicated that circulating γδ T cells are dominated by Vδ2 T cells expressing FcγR III unconstitutively in most health conditions. The expression of FcγR III by human γδ T cells was notably up-regulated when stimulated by antigens, such as human cytomegalovirus, phosphoantigens, and interleukins. The increased expression of FcγR III by γδ T cells enhances the ADCC effect and lytic activity on infected cells and tumor cells and leads to tumor necrosis factor (TNF)-α production.

The γδ T cell FcγR III has already been extensively explored for immunotherapy development. Treatment with antibodies specific to target tumor antigens, such as rituximab and trastuzumab, can enhance FcγRIII‑mediated ADCC on target tumors. More importantly, the binding of γδ T cell FcγR III to various antibodies can be used for the development of bispecific γδ T cell antibodies, an effective method for γδ T cell immunotherapy improvement by engaging effector γδ T cell to target tumor cells.

Fig.2 Mechanism underlying γδ T cell killing of tumors. (Gogoi, 2013)

References

1. Bournazos, S., et al. The role of IgG Fc receptors in antibody-dependent enhancement. Nature Reviews Immunology. 2020, 1-11.
2. Gogoi, D., Chiplunkar, S.V. Targeting gamma delta T cells for cancer immunotherapy: bench to bedside. Indian Journal of Medical Research. 2013, 138(5): 755-761.