Multifaceted roles of Fcγ receptors in COVID-19 and vaccine responses

Abstract

Recent data have revealed various effector functions of FcγRs in immune responses against challenges with SARS-CoV-2 virus. FcγRs act as a bridge between antibody specificity and effector cells. In many cases, IgG/FcγR interactions generate cell-mediated immune protection from infection via ADCP or ADCC. These responses are beneficial, as they may participate in virus elimination and persist longer than neutralizing anti-Spike antibodies. In contrast, these interactions may sometimes prove beneficial to the virus by enhancing viral uptake into phagocytic cells via ADE and causing excessive inflammation. Here, we summarize key features of FcγRs, discuss effector functions, clinical relevance, and factors influencing FcγR-mediated immune responses in COVID-19 and vaccine responses, and consider IVIg and kinase inhibitors for targeting FcγRs signaling in COVID-19.

Keywords: ADCC; ADCP; ADE; Fc glycosylation; FcγR; SARS-CoV-2; vaccination.

Figure 1

FcγRs signaling (LEFT), the cross-linking by anti-SARS-CoV-2 IC of activating FcγRs induces phosphorylation of the tyrosine residues within ITAM motif by Src-family kinases, leading to the activation of Syk and recruitment of Btk and PLCγ that induce downstream signaling and cellular activation (RIGHT), Abs present in serum from severe COVID-19 patients induce inhibitory FcγRIIb signaling through phosphorylation of the tyrosine present within the ITIM motif by Lyn responsible for the recruitment of inositol phosphatases (SHP), which inhibits ISGs expression following IFNAR engagement. Syk: Spleen tyrosine kinase; PLCγ: Phospholipase C gamma 1; Btk: Bruton’s tyrosine kinase; PI3K: phosphoinositide 3-kinase; PKC: protein kinase C; IFNAR: Interferon-α/β receptor; ISGs: IFN-stimulated genes.

Figure 2

Fcγ receptors effector activities during SARS-CoV-2. Abs against SARS-CoV-2 are able to deploy a plethora of FcγRs effector activities over the course of Covid-19. These include but are not limited to the following: 1) The stimulation of NK cell degranulation to kill infected cells by ADCC. 2) The stimulation of macrophage opsonophagocytosis by ADCP. 3) The ADE by enhanced viral uptake via FcγRIII-mediated endocytosis into CD16+ monocytes causing overstimulation of inflammasome without net viral replication. FcγRs: Fc gamma Receptors; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2 virus; Nab: neutralizing-antibody; ACE2: angiotensin-converting enzyme 2; ADCP: antibody-dependent cellular phagocytosis; ADCC: antibody-dependent cellular cytotoxicity; DCs: dendritic cells; ADE: antibody-dependent enhancement.

Figure 3

Factors that may affect FcγR-mediated effector functions in COVID-19 and vaccine responses. The ability of binding between IgG Abs and FcγRs to result in FcγR-mediated effector functions is affected by several factors, including the antibody isotype and subclass selection, the antibody Fc glycosylation, genetic variation of FcγRs, vaccine regimen (antigen, adjuvant and doses) and age. These factors dictate the likelihood of producing either a protective response to vaccination and infection or an undesirable excessive inflammatory reaction.