Chien, Y.-h. | Search bioRxiv

bioRxiv2025

Cytokine Regulation of Human Antibody Responses to Influenza Vaccines

Studies show that human vaccine responses widely vary. Here, we analyzed data measuring 66 cytokines from 4 different inactivated influenza vaccine (IIV) cohorts over 5 seasons (N=581) and identified a significant correlation between baseline/day 0 serum IL-18 and IFN-{beta} concentrations and the vaccine-specific antibody response on day 28, suggesting these factors may have an adjuvant-like effect. To investigate this further, we tested the impact of 19 cytokines on the development of anti-influenza antibody response when administered together with the IIV vaccine in human tonsil and spleen organoids. We found that Type I IFNs (IFN-{beta} and others), IL-21, IL-12, IL-10, but not IL-18 or IFN-{gamma}, enhanced the antibody response. The live attenuated influenza vaccine (LAIV) induced a stronger antibody response than the inactivated one in organoids. Adding a single cytokine, IFN-{beta}, to IIV stimulation recapitulated most of the live vaccine-specific cytokine activation program. It increased the antibody response of the inactivated vaccine to that of the LAIV. Two other antibody-boosting cytokines, IL-12 and IL-21, were induced by LAIV but not by Type I IFNs, indicating different cytokines can affect different pathways leading to a robust antibody response. We then generated cytokine mRNA lipid nanoparticles (LNPs) to test the effect of cytokines on IIV response in a mouse model of immunization. We found that IL-21-LNPs augmented the quantity and breadth of the antibody responses, while IFN-{beta} LNPs enhanced durability. These findings identified parallel cytokine pathways regulating human vaccine responses and provide a rationale for using cytokines as adjuvants to mimic the effectiveness of live-attenuated vaccines without the risk of viral replication.

immunology↗

bioRxiv2021

The role of antigen recognition in the γδ T cell response at the controlled stage of M. tuberculosis infection.

{gamma}{delta} T cells contribute to host immune defense uniquely; but how they function in different stages (e.g., acute versus chronic) of a specific infection remains unclear. As the role of{gamma}{delta} T cells in early, active Mycobacterium tuberculosis (Mtb) infection is well documented, we focused on elucidating the{gamma}{delta} T cell response in persistent or controlled Mtb infection. Systems analysis of circulating{gamma}{delta} T cells from a South African adolescent cohort identified a distinct population of CD8+{gamma}{delta} T cells that expanded in this state. These cells had features indicative of persistent antigenic exposure but were robust cytolytic effectors and cytokine/chemokine producers. While these{gamma}{delta} T cells displayed an attenuated response to TCR-mediated stimulation, they expressed Natural Killer (NK) cell receptors and had robust CD16 (Fc{gamma}RIIIA)-mediated cytotoxic response, suggesting alternative ways for{gamma}{delta} T cells to control this stage of the infection. Despite this NK- like functionality, the CD8+{gamma}{delta} T cells consisted of highly expanded clones, which utilized TCRs with different V{gamma}/{delta} pairs. Theses TCRs could respond to an Mtb-lysate, but not to phosphoantigens, which are components of Mtb-lysate that activate{gamma}{delta} T cells in acute Mtb infection, indicating that the CD8+{gamma}{delta} T cells were induced in a stage-specific, antigen-driven manner. Indeed, trajectory analysis showed that these{gamma}{delta} T cells arose from naive cells that had traversed distinct differentiation paths in this infection stage. Importantly, increased levels of CD8+{gamma}{delta} T cells were also found in other chronic inflammatory conditions, including cardiovascular disease and cancer, suggesting that persistent antigenic exposure may lead to similar{gamma}{delta} T cell responses.

immunology↗