"A vaccine changes the landscape of a node in hours": how different vaccines "rewire" the stromal cells of lymph nodes

We usually talk about lymphocytes and antibodies, but the first blow of the vaccine is not taken by the "immune system" at all, but by the stromal cells of the draining lymph nodes - the tissue framework, road network and "signal beacons" for leukocytes. In Science Immunology they showed: the type of vaccine (mRNA, adenovector or protein) reprograms these cells differently and very quickly - even before dendritic cells with antigen arrive at the node. This changes the collection and transport of antigens from the lymph, the formation of chemokine gradients and even the "traffic" of eosinophils inside the node.

Background of the study

Most of the talk about vaccination revolves around B and T cells, but the first “scene” of the immune response is played out at the tissue level of the draining lymph node. Its stroma – primarily lymphatic endothelial cells (LECs) and fibroblastic reticular cells (FRCs) – forms the scaffolding of the node, lays down chemokine “pathways,” and filters antigens flowing in with the lymph from the injection site. It is in this microenvironmental landscape that it is decided how quickly and of what quality the adaptive response will assemble: where B-cell germinal centers will appear, how T-cell zones will be distributed, which innate cells will be “called” first.

Current vaccine platforms vary greatly in how they interact with tissues at the start. Lipid nanoparticles with mRNA can briefly transfect cells in the node and provide local antigen production; adenovector constructs carry DNA and are also able to directly “reach” non-immune cells; protein subunit vaccines more often rely on an adjuvant, antigen capture and its transfer by migrating dendritic cells. These differences promise not only different response amplitudes, but also different “first hours”: who exactly sees the antigen, which genes the stroma turns on, how transport from the sinuses to the parenchyma of the node changes.

Historically, early events after vaccination have been viewed as a sequence of “injection → local inflammation → arrival of dendritic cells with antigen → initiation of an adaptive response.” However, accumulated data suggest a more complex picture: the tissue elements of the node itself are not passive - they quickly respond to the carrier and composition of the vaccine, changing the expression of adhesion molecules, chemokines, and antigen utilization/transfer pathways. Such “reprogramming” can shift the balance between antibody and T-cell immunity, determine the strength and duration of memory, and explain why some formulations work better with revaccination, while others work better with primary vaccination.

For vaccinology, this shifts the focus from “which antigen to show” to “in which microlandscape to see it.” Understanding how different platforms reconfigure LECs and FRCs in hours opens the door to more precise design of adjuvants, booster intervals, and targeting of specific stromal niches—to control the quality of the immune response not only through composition but also through tissue context.

What did they do?

• Mice were immunized with clinically used mRNA-LNP, adenovector and protein vaccines against SARS-CoV-2 S protein.
• The draining lymph nodes were examined multimodally: bioimaging, single-cell transcriptomics and functional tests.
• The focus was not on lymphocytes, but on the stroma: lymphatic endothelial cells (LECs) and fibroblastic reticular cells (FRCs).

Key observations

• mRNA and adenovector vaccines directly transfect LEC and FRC subtypes in vivo and trigger early local S protein production at the node, with variations by vaccine type.
• Already in the first hours, transcriptome reprogramming of the stroma occurs, which changes:
  • sanitation/transfer of lymphatic antigens to the parenchyma of the node;
  • chemokine gradients;
  • migration of eosinophils through the node network.
• An important correction of expectations: the stroma “wakes up” before 12 hours, that is, before the arrival of migrating dendritic cells - the classic picture of events after injection needs to be redrawed.

Why is this important?

The first "decisions" about how the immune response will unfold are made at the level of the host tissue. If different vaccine platforms tune LEC/FRC differently, then we have an explanation for why some formulations pull the T-cell response more strongly, while others pull the antibody response more strongly, and how adjuvants/timing of booster shots can bias this. This shifts the focus from "what to show the immune system" to "what landscape will it see it in?"

A bit of mechanics

• LEC and FRC are the “road builders” and “dispatchers” of the node: they filter antigens from the lymph, pull chemokine pathways along themselves, and maintain the “tone” of the tissue.
• When the carrier/platform delivers the S-protein directly to these cells, they change their program: in some places they better select and transmit the antigen further, in others they more strongly “call” the necessary leukocytes.
• The result is a different starting stage for B and T cells, even before their mass assembly at the node.

What does this mean for vaccine development?

• Stromal targeting: Stromal subtypes have different roles; formulations can be more precisely targeted (e.g., specific LEC niches).
• Adjuvants and schedules: if we know what kind of “reprogramming” the platform gives in the first hours, we can select an adjuvant and booster interval to catch the optimal window.
• Early response marker panel: LEC/FRC transcriptomic signatures in nodes - candidates for response quality biomarkers already in the first day after injection.

Important Warnings

• The work is about mechanisms, not about comparing the efficacy/safety of specific vaccines in the clinic; the model is mouse. The authors separately emphasize that they used COVID vaccines only as a convenient platform for studying early tissue events.
• Translocation to humans requires biopsies/imaging of nodes and validated surrogates (blood markers of stromal activation).

Facts and figures worth remembering

• The events start in the first hours after the injection, not half a day later.
• LEC/FRC are the first recipients of the vaccine load at the node for mRNA and adenovector platforms.
• Effects include antigen scavenging, parenchymal transfer, chemokines, eosinophils - all of which change the "scene" for the adaptive response.

Conclusion

The study shifts the focus from immune cells to the tissue “orchestra pit” of the lymph node: it is the stroma that first encounters the vaccine and sets the tone for the entire response – and in different ways for mRNA, adenovector, and protein antigen. Understanding this early “reprogramming” gives vaccinologists another lever – to control the landscape of the node, and therefore the quality of immune memory.

Source: Fair-Mäkelä R. et al. COVID-19 vaccine type controls stromal reprogramming in draining lymph nodes. Science Immunology, August 15, 2025. DOI: 10.1126/sciimmunol.adr6787