Louise M. C. Webb

Vaccine responses are impaired in aged mice and older people. A key first step in mounting successful responses to vaccines is for antigens to access the draining lymph node from the site of injection. Here we tested the hypothesis that nanoparticle drainage to the lymph node is impaired in older mice after intramuscular injection. We observed fewer 20 nm nanoparticles in the draining lymph node in aged mice after intramuscular injection. However, there was no significant difference in the abundance of larger 1000 nm particles in the lymph nodes of aged mice, which are typically transported to the lymph node by antigen presenting cells. This impaired nanoparticle access was associated with changes in lymph node stromal cells, and a reduction in lymphatic endothelial cells in aged mice. These data suggest that access of smaller antigens to the lymph node may be impaired in ageing and may have implications for the initiation of T and B cell responses after vaccination.

The germinal center (GC) is the engine room of the humoral immune response, driving the evolution of B cells into memory and long‐lived plasma cells that can protect against (re)infection. Understanding GC biology remains a key research focus for promoting lifelong health. In this annual update, we highlight several influential studies on GC biology published in 2025 (Fig. 1). Space constraints prevent us from discussing in depth all published work.

Vaccines stimulate protective humoral immunity by coordinating lymphocyte activity in the germinal center (GC) response. However, the degree of protection varies across the population, with older individuals often showing lower titer antibody responses to vaccines. Previous work has correlated increased exposure to Th1 cytokines, like IL‐2, with poor antibody responses in aging. Whether this is a causal relationship is unknown. Here we used Il2 ^cre/+ ; Rosa26 ^{stop‐flox‐Il2/+} mice, which cannot shut down IL‐2 production once initiated, to test the hypothesis that sustained IL‐2 exposure affects the GC response and antibody production post vaccination. Prolonged IL‐2 production impeded T follicular helper (Tfh) cell differentiation, with reduced numbers of GC Tfh, pre‐Tfh and T follicular regulatory cells consistently observed in the draining lymph node of Il2 ^cre/+ ; Rosa26 ^{stop‐flox‐Il2/+} mice at day 10 post immunization, relative to control mice. Numbers of Tfh cells remained suppressed at day 21 post immunization and corresponded with reduced GC B cell formation, including NP‐specific IgG1 ⁺ class‐switched GC B cells. As a core output of the GC response, B220 ⁻ IRF4 ⁺ CD138 ⁺ antibody‐secreting cells (ASCs) were significantly reduced in the bone marrow of Il2 ^cre/+ ; Rosa26 ^{stop‐flox‐Il2/+} mice, 10 days post NP‐KLH immunization compared to control mice. However, by day 21, antigen‐specific humoral immunity was restored, with similar levels of B220 ⁻ IRF4 ⁺ CD138 ⁺ and NP‐specific ASCs in both experimental and control groups. In summary, while sustained IL‐2 production delayed Tfh differentiation and early GC formation, it did not affect overall antibody titers after vaccination.

T follicular helper (Tfh) cells are critical for germinal centers (GC), the specialised microenvironment where long-lived humoral immunity is generated in response to vaccination or infection. Within the GC, B cells engage with Tfh cells and elicit their help in the form of cytokines and cell-surface co-stimulator molecules. Tfh helper activity must be rapidly available in response to B cell engagement, yet the mechanisms controlling this helper activity remain poorly characterized. Post-transcriptional regulation of mRNA decay and translation offer one way to rapidly and temporally tune Tfh cell activity. ZFP36L1, a member of the ZFP family of RNA-binding proteins, is a candidate modulator of Tfh cell helper activity as it controls cytokine production and responses in other T cell lineages, modulating their differentiation and function. We sought to determine if ZFP36L1 is also important for Tfh cell biology. In this study, we show expression of ZFP36L1 by Tfh cells. We selectively delete ZFP36L1 from Tfh cells and analyze the effect this has on the GCs. Surprisingly, we find the GC response and affinity maturation is resilient to deletion of ZFP36L1 from Tfh cells.

Vaccine responses are impaired in aged mice and older people. An essential early step in mounting successful responses to vaccines is the delivery of antigens from the site of injection to the draining lymph node. This study tested the hypothesis that particle drainage to the lymph node is impaired in older mice after intramuscular injection. We observed fewer 20nm nanoparticles in the B cell follicle of the draining lymph node in aged mice after intramuscular injection. However, there was no significant difference in the abundance of larger 1000nm particles in the lymph nodes of aged mice, which are typically transported to the lymph node by antigen presenting cells. This data suggests that access of smaller antigens to the B cell follicle is impaired in ageing and may have implications for the initiation of T and B cell responses after vaccination.

T follicular helper (T _FH ) cells are essential for germinal center (GC) formation and long-lived humoral immunity. Here, we used an Il21 fate mapping (Il21-fm) strategy to remove T _FH cells from established GCs to disentangle their function from that of other T cells in a temporal manner. We confirm their role in driving proliferation and positive selection of GC B cells but show that GCs can survive the transient absence of T _FH cells. After ablation of T _FH cells, both the GC response and affinity maturation recover via ingress of new T _FH cells. Despite recovery of the B cell response, T _FH cell numbers are never fully restored. This feeds through into the T cell memory response, resulting in diminished recall GC responses. This work shows an unappreciated resilience of primary GC responses to perturbations in T _FH cells and demonstrates critical memory T cell generation during this phase.

Background: Influenza remains a significant threat to human and animal health. Assessing serological protection against influenza has relied upon haemagglutinin inhibition (HAI) assays, which are used to gauge existing immune landscapes, seasonal vaccine decisions and in systems vaccinology studies. HAI assays were first described in the 1940s. Here, we adapt our high‐throughput live virus microneutralisation (LV‐N) assay for SARS‐CoV‐2, benchmark against HAI assays, and report serological vaccine responsiveness in a cohort of older (> 65 yo) community dwelling adults.Methods: Influenza‐specific antibody responses were assessed in 73 individuals, before and after receipt of the adjuvanted 2021–22 Northern Hemisphere quadrivalent vaccine. We performed both HAI and LV‐N assays against all four viruses represented in the vaccine [A/Cambodia/e0826360/2020 (H3N2), IVR‐215 (A/Victoria/2570/2019‐like) (H1N1)pdm09, B/Phuket/3073/2013 (B/Yamagata lineage), B/Washington/02/2019 (B/Victoria lineage)], using sera drawn before vaccination [range: d‐82 to d‐5], and days 7 [d6–10] and 181 [d156–200] after vaccination. We compared serological responses within each assay and between assays.Results: Both the traditional HAI assay and our high‐throughput live virus microneutralisation identified vaccine‐induced boosts in antibody titres. We found population‐level concordance between the two assays (Spearman's correlation coefficient range 0.49–0.88; all p ≤ 1.4 × 10⁻⁵). The improved granularity of microneutralisation was better able to estimate fold changes of responses and quantify the inhibitory effect of pre‐existing antibody.Conclusions: Our high‐throughput method offers an alternative approach to assess influenza‐specific serological responses with improved resolution, with the potential to improve the annual assessment of existing antibody landscapes, to improve new vaccine strain evaluation, and to offer a step‐change in systems vaccinology, and a facet of laboratory‐based pandemic preparedness.

T follicular helper (T_FH) cells are a helper T‐cell subset that is defined by their localisation to B‐cell areas of secondary lymphoid tissues, enabling them to provide their B‐cell helper function. Precursors of T_FH cells migrate to the B‐cell follicles by upregulating CXCR5 and downregulating CCR7, a process that can be blocked by S1PR1 overexpression. T_FH cells and their precursors also express the early activation antigen CD69, which is a negative regulator of S1PR1. In this study, we tested the hypothesis that CD69 expression by T_FH cells is important for their differentiation and localisation after immunization. Genetic deletion of CD69 on T_FH cells and a proportion of their precursors did not alter their formation, nor their ability to support high‐affinity B‐cell responses. This demonstrates that although CD69 is expressed highly on T_FH cells, it is not necessary for their formation or their B‐cell helper functions in lymph nodes (LNs).

Ageing profoundly changes our immune system and is thought to be a driving factor in the morbidity and mortality associated with infectious disease in older people. We have previously shown that the impaired immunity to vaccination that occurs in aged individuals is partly attributed to the effect of age on T follicular helper (Tfh) cell formation. In this study, we examined how age intrinsically affects Tfh cell formation in both mice and humans. We show increased formation of Tfh precursors (pre‐Tfh) but no associated increase in germinal centre (GC)‐Tfh cells in aged mice, suggesting age‐driven promotion of only early Tfh cell differentiation. Mechanistically, we show that ageing alters TCR signalling which drives expression of the Notch‐associated transcription factor, RBPJ. Genetic or chemical modulation of RBPJ or Notch rescues this age‐associated early Tfh cell differentiation, and increased intrinsic Notch activity recapitulates this phenomenon in younger mice. Our data offer mechanistic insight into the age‐induced changes in T‐cell activation that affects the differentiation and ultimately the function of effector T cells.