Journal of Vaccine Research 2024, Vol.14, No.6, 297-306 http://medscipublisher.com/index.php/jvr 299 Figure 1 The range of abundance and functional capacity of influenza-specific human CD4 T cells within different subjects (Adopted from Sant et al., 2018) Image caption: Existing data from PBMC from healthy donors indicates a broad range in frequency of influenza-specific CD4 T cells. Shown here for illustration are the differences depicted as bar heights, reflecting the total abundance of influenza specific CD4 T cells. The frequency of each functionally distinct subset of cells are indicated by different colored segments within each bar. This theoretical representation reflects the extreme view that there are nonoverlapping subsets of CD4 T cells that convey each of indicated functions. Thus far, only the strict dichotomy between cytolytic cells and Tfh cells is supported by their unique and opposing transcription factors. In the example shown, subject 2 and subject 4 have similar frequencies of influenza-specific CD4 T cells, but may be poised differently for protective immunity. Subject 2, having more abundant cytolytic cells might be best protected from infection by eliminating infected cells, while subject 4, with high frequency of Tfh cells, would exhibit the more robust antibody response. The right pie diagrams illustrate that in provision of help for B cell responses, in Subject 4, the antigen specificity of the CD4 T cells is critically important in providing help. The neutralizing antibody response to vaccination would likely vary, depending on the abundance of HA-specific Tfh cells drawn into the response, with different outcomes depending on whether Subject 4 had high (top) or low (bottom) levels of HA-specific CD4 T cells. It is not yet known whether other functions of CD4 T cells, such as recruitment of innate effectors to the lung, or cytotoxicity, tracks with their antigen specificit (Adopted from Sant et al., 2018) However, the efficacy of CD8+ T cells depends on the assistance of CD4+ T cells. When there is a lack of CD4+ support, the localization ability of pulmonary CD8+ T cells (decreased expression of CD103) and the recruitment efficiency of reinfection will significantly decline. Studies have shown that IFN-γ secreted by CD4+ is crucial for generating protective CD103+CD8+ T cell populations, revealing the synergistic relationship between the two in respiratory immunity (Laidlaw et al., 2014). 3.3 Characteristics of memory T cells CD4+ and CD8+ memory T cells provide long-term protection through multiple mechanisms. Whether it is memory cells induced by natural infection or vaccination, they can respond rapidly to seasonal and pandemic strains. Memory CD4+ subsets not only accelerate viral clearance through direct effect function, but also coordinate pulmonary immune responses independently of traditional auxiliary functions (Teijaro et al., 2010). The formation of memory cells is influenced by the time of antigen exposure, the frequency of stimulation and the cytokine environment. If influenza convalescent proteins are targeted specifically during vaccine design, the generation of memory cells can be optimized, thereby enhancing the durability of protection (Swain et al., 2006). An in-depth analysis of these mechanisms is of great significance for the development of a new generation of vaccines. 4 The T-cell Strategy of Universal Influenza Vaccines 4.1 Target conserved viral components The development of universal vaccines is undergoing a strategic transformation - from targeting mutatable surface proteins to the stable structures within the virus. The research focus has shifted to highly conserved components such as nucleoproteins (NP) and matrix proteins, which can activate cross-immune responses across influenza
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