Mucosal vaccination with TLR9 agonists promote the development of tissue resident helper cells and mucosal humoral immunity against influenza 2259178

Abstract Introduction Current influenza (flu) vaccination strategies rely on accurate prediction of the circulating strains for the upcoming season. Therefore, the induction of a cross-reactive memory response is desirable. Tissue resident helper (Trh) cells are a population T follicular helper (Tfh)-like CD4+ tissue resident memory T cells induced by flu infection that promote the development of tissue resident memory B (Brm) cells. Vaccination strategies that induce Trh cell differentiation may prove useful in the development of cross-reactive immunity to flu infections, however no such adjuvant formulation is known to accomplish this. Methods Using an intranasal immunization strategy with the conserved influenza A nucleoprotein (NP), we screened multiple adjuvants for their ability to induce Trh cell, Brm cell and airway antigen specific IgG2c and IgA development. Utilizing a conditional knockout model, we investigated the role of T cell -intrinsic TCF-1, a transcription factor required for Tfh cell differentiation, in the development Trh cell and mucosal B cell responses following intranasal vaccination. Utilizing human tonsil organoids to model the , we investigated the the ability of of CpG ODN to promote the human adaptive immune response. Results The TLR9 agonist CpG ODN induced Trh cell development which was associated with the induction of lung resident GC B cells, CXCR3+ Brm cells and NP-specific IgG2c and IgA in the airways, which was dependent on T cell-intrinsic TCF-1. Mice intranasally immunized with CpG ODN and NP, or other conserved and variable antigens, were protected against lethal challenge from both H1N1 and H3N2 flu strains. In human tonsil organoids, CpG ODN could promote the differentiation of plasmablasts. Conclusion Together, our data indicates mucosal immunization with CpG ODN promotes the development of Trh cells, mucosal B cell responses, and protection against multiple strains of influenza A. This work has implications for the development of universal flu vaccines Funding Source R01 AI151139 Topic Categories Vaccines and Immunotherapy (VAC)