Lack of Fc Gamma Receptor IIIA Promotes Rather than Suppresses Humoral and Cellular Immune Responses after Mucosal or Parenteral Immunization with Antigen and Adjuvants

Abstract

The Fcγ receptor IIIA (FcγRIIIA) has traditionally been known as a positive regulator of immune responses. Consistent with this, mice deficient in FcγRIIIA are protected from various inflammation-associated pathologies including several autoimmune diseases. In contrast to this accepted dogma, we show here that mice lacking FcγRIIIA developed increased rather than reduced both humoral and cellular immune responses to mucosal (sublingual) immunization with ovalbumin (OVA) given together with the strong mucosal adjuvant cholera toxin as well as to parenteral (subcutaneous) immunization with OVA in complete Freund's adjuvant. After either route of immunization, in comparison with concomitantly immunized wild-type mice, FcγRIIIA mice had increased serum anti-OVA IgG (IgG1 but not IgG2) antibody responses as well as augmented cellular responses that included memory B cells and effector T cells. The increments in immune responses in FcγRIIIA mice were similar to those seen in FcγRIIB mice. Furthermore, OVA-pulsed FcγRIIIA DCs, similar to OVA-specific FcγRIIB DCs, had enhanced capacity to activate OVA-specific OT-II T cells, which was even further pronounced when DCs were pulsed with IgG1-complexed OVA. Our data support an inhibitory-regulatory role of FcγRIIIA on vaccine/adjuvant-induced immune responses and demonstrate that lack of FcγRIIIA can promote rather than suppress both humoral and cellular immune responses.

Recent Advances in Experimental Allergy

“…It was found that FcγRIIB negatively correlated with serum IgE; however, this was not the case for FcγRIIIA [19]. Interestingly, unlike previously published work [20-22], the work of Zhou et al [19] did not support the positive immune regulatory roles of mouse FcγRIIIA.…”

Intestinal Radiation Protection and Mitigation by Second-Generation Probiotic Lactobacillus-reuteri Engineered to Deliver Interleukin-22

“…The small intestine is known to be significantly radiosensitive compared to the large intestine [ 1 , 2 , 3 , 4 ], and, thus, has been studied as the target for delivery of oral/gavage administration of radiation protectors/mitigators. Specific functions of the microbiome are known to be critical for intestinal radiation protection by providing both metabolic functioning and detoxification of deleterious by-products of metabolism, which are important for intestinal radiation protection [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ].…”

“…Recent attention has focused on the potential importance of anerobic bacterial taxa, including Bacteroides, on intestinal health and recovery from systemic toxins including ionizing irradiation [ 22 , 28 , 29 , 30 ]. The use of E. coli and particular sub-strains genetically engineered to produce specific small molecules has been tested as a therapeutic probiotic for the treatment of colon cancer [ 34 ].…”

FcγRIIIA Negatively Impacts Humoral Immune Responses but Not Overall Lung Inflammation in an Ovalbumin-Induced Allergic Asthma Mouse Model

“…A recent study revealed an immune inhibitory role of FcγRIIIA in mice after sublingual immunization adjuvanted by cholera toxin [12], although we previously demonstrated that FcγRIIIA played an immune activatory role in a mouse mucosal immunization model by exploiting mast cell activation [24]. We believe that FcγR-mediated regulation of immune responses involves complex regulatory pathways and the exact roles of FcγRIIIA may depend on the specific models.…”

“…Interestingly, established stereotypes about Fc receptors have been challenged when emerging evidence argues for immune inhibitory responses stemming from ITAM-containing Fc receptors including FcγRIIIA, and such ITAM that transduces inhibitory signals is specifically addressed as ITAMi [9][10][11]. It has recently been revealed that FcγRIIIA -/-mice augment rather than suppress both humoral and cellular immune responses following cholera toxin-adjuvanted mucosal immunization [12].…”