Integrin-mediated regulation of type-1 dendritic cell positioning and function in lymph nodes

Despite significant advances in understanding antigen-presenting cells (APCs) and their roles in adaptive immunity, the mechanisms that optimize their function in tissue surveillance and antigen sampling remain elusive. This is particularly critical in cancer, where effective tumor antigen presentation in lymph nodes (LNs) necessitates the coordinated efforts of diverse dendritic cell (DC) populations. Migratory DCs transport tumor antigens to LNs, while LN-resident DCs (DC1) specialize in initiating CD8 T cell responses. This project explores two previously underappreciated aspects of LN-resident DC1 biology: the molecular regulation of their positioning in LNs via integrins, and the impact of this positioning on interactions with migratory DCs for efficient antigen transfer and generation of robust anti-tumor T cell responses. We previously discovered that DC subsets inhabit distinct regions in LNs, with LN-resident DC1 preferentially localizing in the T cell zone and near blood vessels. The molecular regulation and function of this distribution is unknown. Our preliminary data now indicate that DC1 positioning near blood vessels is regulated by the integrin, CD11a. We hypothesize that CD11a facilitates DC1 tethering to blood vessels and perivascular migratory DCs, both rich in CD11a ligands, thus coordinating DC subset organization in LNs. Our data also shows that CD11a integrin enables LN-resident DC1 to interact with migratory DCs. Previous studies have shown that in cancer, migratory DCs are required to transport tumor antigens into LNs, where they hand-off these antigens to LN-resident DC1 for cross-presentation and generation of anti-tumor CD8 T cell responses. While integrins are known to support this process via exosomes, the spatial dynamics of how this occurs in vivo and the specific role of CD11a integrin in antigen transfer to LN-resident DC1 in settings of cancer remains unknown. Therefore, our data raise an exciting hypothesis that by enabling interactions of LN-resident DC1 with migratory DCs, CD11a enhances antigen hand-off and promotes robust induction of anti-tumor T cell immunity. This project employs cutting-edge imaging and genetic techniques to address three specific aims: 1) Elucidate the role of CD11a in regulating LN-resident DC1 positioning and cell-cell interactions in both steady- state and tumor-draining LNs; 2) Investigate the role of CD11a in tumor antigen transfer among DC subsets; and 3) Determine the impact of CD11a expression by DC1 on anti-tumor CD8 T cell immunity. By uncovering the molecular and functional mechanisms underlying LN-resident DC1 positioning and function, this research will significantly enhance our understanding of cellular organization in lymphoid organs and its impact on innate- adaptive cell crosstalk necessary for the generation of adaptive immune responses. Moreover, our focus on investigating these processes in cancer settings offers promising translational potential for novel therapeutic strategies aimed at boosting anti-tumor immunity through targeting specific cellular interactions. Project Number: 5R21AI190507-02 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Michael Gerner | Institution: UNIVERSITY OF WASHINGTON, SEATTLE, WA | Award Amount: $220,625 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1-IIDA-U(81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/5R21AI19050702