The TLR5 Agonist Flagellin Shapes Phenotypical and Functional Activation of Lung Mucosal Antigen Presenting Cells in Neonatal Mice

Abstract

Intranasal mucosal vaccines are an attractive approach to induce protective mucosal immune responses. Activation of lung antigen presenting cells (APCs), a phenotypically and functionally heterogeneous cell population located at distinct mucosal sites, may be key to the immunogenicity of such vaccines. Understanding responsiveness of newborn lung APCs to adjuvants may the inform design of efficacious intranasal vaccines for early life, when most infections occur. Here, we characterized and phenotyped APCs from neonatal (7 days of life) and adult (6-8 weeks of age) mice. Neonatal mice demonstrated a relatively high abundance of alveolar macrophages (AMs), with lower percentages of plasmacytoid dendritic cells (pDCs), CD103 + (cDC1), and CD11b + (cDC2) DCs. Furthermore, neonatal CD103 + and CD11b + DC subsets demonstrated a significantly lower expression of maturation markers (CD40, CD80, and CD86) as compared to adult mice. Upon stimulation of lung APC subsets with a panel of pattern recognition receptor (PRR) agonists, including those engaging TLRs or STING, CD11c + enriched cells from neonatal and adult mice lungs demonstrated distinct maturation profiles. Of the agonists tested, the TLR5 ligand, flagellin, was most effective at activating neonatal lung APCs, inducing significantly higher expression of maturation markers on CD103 + (cDC1) and CD11b + (cDC2) subsets. Intranasal administration of flagellin induced a distinct migration of CD103 + and CD11b + DC subsets to the mediastinal lymph nodes (mLNs) of neonatal mice. Overall, these findings highlight age-specific differences in the maturation and responsiveness of lung APC subsets to different PRR agonists. The unique efficacy of flagellin in enhancing lung APC activity suggests that it may serve as an effective adjuvant for early life mucosal vaccines.

Harnessing innate immunity to eliminate SARS-CoV-2 and ameliorate COVID-19 disease

“…Besides promoting antibody production, flagellin is important for the maturation of lung dendritic cells (14), inhibition of epithelial apoptosis (44), production of IL-17C cells (36), and induction of cathelicidindependent antimicrobial responses (49), all of which coincide with the essential nature of flagellin's mucosal adjuvant activity. It is noteworthy that flagellin was found to be very effective in activating neonatal lung antigen-presenting cells (40). Furthermore, flagellin-TLR5 activation was observed to protect mice from invasive pneumonia through early clearance of Pseudomonas aeruginosa in respiratory epithelial cells (2,32).…”

Environmental signals rather than layered ontogeny imprint the function of type 2 conventional dendritic cells in young and adult mice

“…Although CD8 expression does not reliably distinguish cDC1 and cDC2 in neonatal spleen 17,34 , these data suggest a reduced ability of neonatal cDC2 to activate T cells. Similarly, cDC2 in neonatal lung express lower costimulatory molecules than adult cDC2 32,[35][36][37] , although they can promote Th2mediated allergy and induce some CD8 + T-cell proliferation when infected with respiratory syncytial virus 30,32,38 . These data indicate that in early life, cDC2 have the potential to activate T cells in some circumstances, raising the question whether this capacity could be harnessed in a broader sense, for instance to initiate T-cell responses in the spleen, which is a major site for antibody production 39 .…”

The role and research progress of the balance and interaction between regulatory T cells and other immune cells in obesity with insulin resistance

“…Dendritic cells (DCs) have the unique ability to initiate T cell responses and play a key role in coordinating adaptive immune responses [ 67 ]. In both mice and humans, DCs are divided into conventional dendritic cells (cDCs) and plasma cell-like dendritic cells (pDCs) according to differences in their transcription and functions, with the former including CD103 (cDC1) and CD11b (cDC2) subsets [ 68 , 69 ].…”