Spatial dysregulation of T follicular helper cells impairs vaccine responses in aging

Abstract

The magnitude and quality of the germinal center (GC) response decline with age, resulting in poor vaccine-induced immunity in older individuals. A functional GC requires the co-ordination of multiple cell types across time and space, in particular across its two functionally distinct compartments: the light and dark zones. In aged mice, there is CXCR4-mediated mislocalization of T follicular helper (TFH) cells to the dark zone and a compressed network of follicular dendritic cells (FDCs) in the light zone. Here we show that TFH cell localization is critical for the quality of the antibody response and for the expansion of the FDC network upon immunization. The smaller GC and compressed FDC network in aged mice were corrected by provision of TFH cells that colocalize with FDCs using CXCR5. This demonstrates that the age-dependent defects in the GC response are reversible and shows that TFH cells support stromal cell responses to vaccines.

Adaptive immunity and atherosclerosis: aging at its crossroads

“…In line with this finding, Silva-Cayetano et al. have shown that following immunization with NP-KLH, a model antigen to assess vaccine responses, an aging-associated decrease in germinal center formation and quality of antibody responses was observed through spatial dysregulation of Tfh cells in BALB/c mice ( 175 ). Aged Tfh cells overexpress CXCR4, impeding on their colocalization with FDCs necessary for their priming.…”

“…Additionally, this reduction affects the deposition of IL-7 on the extracellular matrix which is essential for the preservation of naïve T cells ( 179 ). Similarly, SLOs experience a decrease in the area of the light zone alongside the therein contained FDCs necessary for priming Tfh cells ( 175 , 180 ). Overall, these age-related changes impede the correct function and localization of cells from the adaptive immune system and can lead to aberrant germinal center responses.…”

Insights into vaccines for elderly individuals: from the impacts of immunosenescence to delivery strategies

“…Immunosenescence reduces naïve CD4 T cell differentiation into Tfh cells, so there is an insufficient amount of T cells to assist the B cell response 37 . Silva-Cayetano et al found that the expression of CXCR4 increased in Tfh cells from aged mice, while the expression of CXCR5 did not change 38 . The increased expression of CXCR4 led to enhanced chemotaxis of CXCL12 in the dark zone of GC, directly decreased the amounts of antigens presented to B cells, and decreased specific antibody responses.…”

Microbiome-Derived Lipid Nanoparticles for Improved Immunogenicity of mRNA Vaccines

“…Intramuscularly inoculated mRNA vaccines express the antigens and stimulate the nearby lymph node for adaptive immune induction. , Chicken ovalbumin (OVA) has been prevalently employed as a model antigen to evaluate the immunogenicity of nanovaccines . Accordingly, LNPs were prepared with OVA mRNA (mOVA) and intramuscularly injected into the hind leg of mice, and then the inguinal lymph node (iLN) was harvested to measure the immune cell activations 1 and 7 days postinjection (Figure a).…”

“…In addition, inflammatory monocytes, not macrophages, were moderately infiltrated into the iLN of mice injected with B1- or B2-LNPs (Figure e). Follicular helper T cells (FHTs) and germinal center B cells (GCBs) have a crucial role in the development of antigen-specific immunity . At 7 days postinjection, the total number of FHT and GCB cells increased in the iLN of all LNP injected groups, and the B1-LNP group showed the highest number of FHT and GCB cells (Figure f).…”