Retinoic acid‐loaded liposomes induce human mucosal CD103+ dendritic cells that inhibit Th17 cells and drive regulatory T‐cell development in vitro

• Published in: European journal of immunology 2024-05, Vol.54 (5), p.e2350839-n/a
• Main Authors: Nagy, Noémi Anna, Hafkamp, Florianne M. J., Sparrius, Rinske, Bas, Rico, Lozano Vigario, Fernando, Capel, Toni M. M., Ree, Ronald, Geijtenbeek, Teunis B. H., Slütter, Bram, Tas, Sander W., Jong, Esther C.
• Format: Article
• Language: English
• Subjects: Adjuvants; Aldehyde Dehydrogenase 1 Family; Antigens; Antigens, CD - immunology; Antigens, CD - metabolism; CD103 antigen; Celiac disease; Celiac Disease - immunology; Cell Differentiation - drug effects; Cell Differentiation - immunology; Cell proliferation; Cells, Cultured; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic cells(s); Forkhead Transcription Factors - metabolism; Foxp3 protein; Helper cells; Humans; Immune regulation; Immune Tolerance - drug effects; Immunological tolerance; Immunoregulation; Immunotherapy; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - immunology; Integrin alpha Chains - metabolism; Interleukin-10 - immunology; Interleukin-10 - metabolism; Leukocytes (neutrophilic); Liposomes; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocytes T; Monocytes; Mucosa; Mucosal immunity; Nanoparticles; Phenotypes; Regulatory T cell(s); Retinal Dehydrogenase - metabolism; Retinoic acid; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Th17 Cells - immunology; Tretinoin - pharmacology; Vitamin A
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.202350839

The active vitamin A metabolite, all‐trans‐retinoic acid (RA), primes precursor dendritic cells (DCs) into a mucosal phenotype with tolerogenic properties characterized by the expression of integrin CD103. CD103+ DCs can counteract pathogenic Th1 and Th17 in inflammatory bowel disease (IBD) or celiac disease (CD). Tolerogenic manipulation of DCs using nanoparticles carrying tolerogenic adjuvants and disease‐specific antigens is a valuable treatment strategy to induce antigen‐specific mucosal tolerance in vivo. Here, we investigated the effects of RA‐loaded liposomes on human DC phenotype and function, including DC‐driven T‐cell development, both during the generation of monocyte‐derived DCs (moDCs) as well as by priming immature moDCs. RA liposomes drove CD103+ DC differentiation as well as ALDH1A2 expression in DCs. Neutrophil‐dependent Th17 cell development was reduced by RA‐liposome‐differentiated and RA‐liposome‐primed DCs. Moreover, RA liposome treatment shifted T‐cell development toward a Th2 cell profile. Importantly, RA liposomes induced the development of IL‐10‐producing and FoxP3+ regulatory T cells (Tregs) of various Treg subsets, including ICOS+ Tregs, that were potent inhibitors of bystander memory T‐cell proliferation. Taken together, RA‐loaded liposomes could be a novel treatment avenue for IBD or CD patients. In vitro, RA liposomes drive human monocytes to differentiate into CD103+ mucosal‐like DCs that inhibit Th17 cell development and induce FoxP3+ and IL‐10‐producing T cells. RA liposomes prime human moDCs to shift T‐cell polarization and induce regulatory T cells expressing FoxP3 and IL‐10 in vitro.