Role of T Follicular Helper Cells in Viral Infections and Vaccine Design

Abstract

T follicular helper (Tfh) cells are a specialized subset of CD4+ T lymphocytes that are essential for the development of long-lasting humoral immunity. Tfh cells facilitate B lymphocyte maturation, promote germinal center formation, and drive high-affinity antibody production. Our current knowledge of Tfh interactions with the humoral immune system effectors suggests that they have a critical role in supporting the immune response against viral infections. This review discusses the mechanisms through which Tfh cells influence anti-viral immunity, highlighting their interactions with B cells and their impact on antibody quality and quantity. We explore the role of Tfh cells in viral infections and examine how vaccine design can be improved to enhance Tfh cell responses. Innovative vaccine platforms, such as mRNA vaccines and self-assembling protein nanoplatforms (SAPNs), are promising strategies to enhance Tfh cell activation. Their integration and synergistic combination could further enhance immunity and Tfh responses (SAPN-RNA vaccines). In summary, we provide a comprehensive overview of the current insights into Tfh cells' role during viral infections, emphasizing their potential as strategic targets for innovative vaccine development.

Keywords: B cells; Tfh cells; ferritin; germinal centers; mRNA vaccine; viral infections.

Figure 1

T follicular helper (Tfh) cell differentiation, subsets, and germinal center function. (A) Differentiation of T helper (Th) cell subsets. Interaction between dendritic cells (DCs) and naïve CD4⁺ T cells leads to polarization into Th1, Th2, and Th17 regulatory T cells (Tregs), and Tfh cells, driven by specific cytokines and transcription factors. (B) Subsets of circulating Tfh cells (cTfh). Tfh cells released into circulation (CD4⁺CXCR5⁺) are associated with distinct cytokine profiles and transcription factors such as T-bet, GATA3, RORγt, and Foxp3. (C) Germinal center (GC) Tfh differentiation. Naïve CD4⁺ T cells activated by DCs differentiate into pre-Tfh cells, which migrate to the T-B cell border and interact with activated B cells. In the GC, FDCs and Tfh cells (Bcl-6+, CXCR5+, PD-1+, ICOS+) promote B cell affinity maturation and differentiation into memory and long-lived plasma cells through costimulatory signals mediated by ICOS–ICOSL and CD40–CD40L interactions along with IL-4 and IL-21 cytokine secretion. Without Tfh interaction in GCs, B cells produce low-affinity antibodies as short-lived plasma cells. IL-6 is crucial for Tfh formation in animal models, but not in humans. Created with BioRender.com.

Figure 2

Design and antigen expression mechanism of various mRNA vaccine platforms. (A) Comparison of conventional mRNA, self-amplifying RNA (saRNA), and trans-amplifying RNA (taRNA) vaccine designs. (B) SAPN-RNA vaccine design: Integration of self-assembling protein nanoparticles (e.g., ferritin with 24 subunits) in mRNA vaccines for multivalent antigen display. (C) Key components of lipid nanoparticles (LNPs). (D) Mechanism of action of mRNA vaccines: SAPN-RNA vaccine directly activates naïve B cells and is efficiently processed by antigen-presenting cells, such as dendritic cells (DCs), facilitating Tfh cell activation and differentiation from CD4+ T cells by engaging PRRs, while other formulations mainly rely on LNP adjutant properties. This along with promoting multiple BCR cross-linking and its slow-release properties ensure robust, durable, and stable antibody responses at a lower dose. Cap: m7G; UTR: untranslated region; CSE: conserved sequence element; nsP1–4: alphavirus nonstructural proteins 1–4. Created with BioRender.com.

Figure 3

Schematic structures of natural self-assembling protein nanocages (SAPNs). sHSP: small heat shock protein; MjsHSP16.5 (~16.5 nm, 24-mer; PDB ID: 8WP9); lumazine synthase (~16–24 nm, 60-mer; PDB ID: 8F25) with exposed C- and N-termini on the surface; E2 Dihydrolipoyl Acetyltransferase (~24 nm, 60-mer; PDB ID: 1B5S), ferritin (12 nm, 24-mer; PDB ID: 3BVE); and Encapsulin (20–100 nm, 60-, 180-, or 240-mer; PDB ID: 3DKT). Created with BioRender.com.