Abstract
Long-lived memory cell formation and maintenance are usually regulated by cytokines and transcriptional factors. Adjuvant effects of IL-7 have been studied in the vaccines of influenza and other pathogens. However, few studies investigated the adjuvant effects of cytokines and transcriptional factors in prolonging the immune memory induced by a tuberculosis (TB) subunit vaccine. To address this research gap, mice were treated with the Mycobacterium tuberculosis (M. tuberculosis) subunit vaccine Mtb10.4-HspX (MH) plus ESAT6-Ag85B-MPT64<190–198>-Mtb8.4-Rv2626c (LT70), together with adeno-associated virus-mediated IL-7 or lentivirus-mediated transcriptional factor Id3, Bcl6, Bach2, and Blimp1 at 0, 2, and 4 weeks, respectively. Immune responses induced by the vaccine were examined at 25 weeks after last immunization. The results showed that adeno-associated virus-mediated IL-7 allowed the TB subunit vaccine to induce the formation of long-lived memory T cells. Meanwhile, IL-7 increased the expression of Id3, Bcl6, and bach2—the three key transcription factors for the generation of long-lived memory T cells. The adjuvant effects of transcriptional factors, together with TB fusion protein MH/LT70 vaccination, showed that both Bcl6 and Id3 increased the production of antigen-specific antibodies and long-lived memory T cells, characterized by high proliferative potential of antigen-specific CD4+ and CD8+ T cells, and IFN-γ secretion in CD4+ and CD8+ T cells, respectively, after re-exposure to the same antigen. Overall, our study suggests that IL-7 and transcriptional factors Id3 and Bcl6 help the TB subunit vaccine to induce long-term immune memory, which contributes to providing immune protection against M. tuberculosis infection.
Highlights
Tuberculosis (TB) is one of the global health problems mainly caused by Mycobacterium tuberculosis (M. tuberculosis) infection in humans
The results indicated that the proliferation of CD8+ and CD4+ T cells significantly increased in the vaccine combined with Recombinant adeno-associated viral (rAAV)-IL-7 group (2.23 ± 0.54 and 3.57 ± 0.08 for CD8+ and CD4+ T cells, respectively) than the vaccine alone group (1.19 ± 0.38 and 1.13 ± 0.36 for CD8+ and CD4+ T cells, respectively) or vaccine plus rAAV-EGFP control group (1.05 ± 0.57 and 0.90 ± 0.69 for CD8+ and CD4+ T cells, respectively) following antigen stimulation (Figure 1A–C)
The results indicated that additional rAAV-IL-7, combined with the subunit vaccine, induced more CD8+ long-term memory T cells
Summary
Tuberculosis (TB) is one of the global health problems mainly caused by Mycobacterium tuberculosis (M. tuberculosis) infection in humans. It is believed that BCG induces effector memory T cells (TEM) rather than central memory T cells (TCM), which leads to impaired protective efficiency of BCG in adults [2]. Naïve T cells will develop into effector T cells (Teff) with the CD62L−CD44+ phenotype, TEM with the CD62L−CD44+ phenotype, and TCM with the CD62L+CD44+ phenotype [7,8,9]. Memory T cells, TCM, subsequently remain quiescent following pathogen clearance, and an immune response is exerted more quickly upon stimulation. The development of memory T cells is regulated by the cytokines and transcription factors [8,10,11]. IL-7 has been administered as a vaccine adjuvant, which extends vaccine response and improves the long-term survival of CD8+ memory T cells [17]
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