Deciphering the Role of Human-Fc RI in Cross-Presentation for Optimal CD8 T-Cell Response in the Respiratory Mucosa

About This Grant

PROJECT SUMMARY/ABSTRACT As CD8⁺ T-cell responses are critical to immunity against cancer and cytosolic pathogens, innovative strategies to enhance cross-presentation (XP) and improve CD8⁺ T-cell responses hold great potential for advancing immunotherapies and vaccines for these diseases of major public health concern. Nevertheless, current vaccine technologies predominantly focus on inducing antibody (Ab) responses rather than boosting T- cell-mediated immunity. We have demonstrated that targeting protein antigens (Ags) to human-FcγRI (hFcγRI) can evoke CD8⁺ T-cell responses. However, a critical gap remains in fully understanding the precise role of hFcγRI in promoting XP and CD8⁺ T-cell responses. In this study, we aim to investigate the involvement of hFcγRI in XP and its impact on the ensuing CD8⁺ T-cell responses. Previously, we demonstrated that protein Ags fused to α-hFcγRI elicit CD8 T-cell responses. This prompted our hypothesis that targeting Ags to hFcγRI will promote XP of the targeted Ags leading to enhanced CD8 T-cell mediated immunity. Here we propose to test this hypothesis using a model that integrates an Ab raised against the hFcγRI – named α-hFcγRI, and a mouse strain that expresses hFcγRI on profession antigen presenting cells (APCs). Since we only use the variable fraction (Ab-Fv) of this Ab (without the Fc fraction), this approach allows selective-targeting of hFcγRI without engaging other Fc receptors (FcRs). This is unlike the approaches utilizing immune complexes (ICs) that cannot isolate the role of individual FcRs in XP, due to broad specificity of most Ab isotypes. Additionally, targeting to the activating receptor hFcγRI will induce a more potent response than the ICs - which potentially engage both activating and inhibitory receptors. Moreover, since the expression of hFcγRI is restricted to the professional APCs i.e. Macrophages (MΦs) and Dendritic cells (DCs), it is likely to reduce unwanted activation of other cell types expressing a variety of FcRs. This proposal has two major aims: 1) to investigate the role of hFcγRI-targeting in XP; and 2), to examine the role of various DC subsets in this process, in particular following intranasal delivery of the model vaccine. Overall, this study aims to fill a significant knowledge gap in understanding the role of hFcγRI in XP, which is crucial for enhancing CD8 T-cell responses of protein subunit vaccines. The findings will impact innovative vaccine strategies that effectively promote cell-mediated immunity against cancer and intracellular pathogens, while minimizing unwanted immune activation and inflammation.