Repeated immunization with ATRA-containing liposomal adjuvant transdifferentiates Th17 cells to a Tr1-like phenotype.

In many autoimmune diseases, autoantigen-specific Th17 cells play a pivotal role in disease pathogenesis. Th17 cells can transdifferentiate into other T cell subsets in inflammatory conditions, however, there have been no attempts to target Th17 cell plasticity using vaccines. We investigated if autoantigen-specific Th17 cells could be specifically targeted using a therapeutic vaccine approach, where antigen was formulated in all-trans retinoic acid (ATRA)-containing liposomes, permitting co-delivery of antigen and ATRA to the same target cell. Whilst ATRA was previously found to broadly reduce Th17 responses, we found that antigen formulated in ATRA-containing cationic liposomes only inhibited Th17 cells in an antigen-specific manner and not when combined with an irrelevant antigen. Furthermore, this approach shifted existing Th17 cells away from IL-17A expression and transcriptomic analysis of sorted Th17 lineage cells from IL-17 fate reporter mice revealed a shift of antigen-specific Th17 cells to exTh17 cells, expressing functional markers associated with T cell regulation and tolerance. In the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, vaccination with myelin-specific (MOG) antigen in ATRA-containing liposomes reduced Th17 responses and alleviated disease. This highlights the potential of therapeutic vaccination for changing the phenotype of existing Th17 cells in the context of immune mediated diseases.

Th1/Th17 T cell Tissue-Resident Immunity Increases Protection, But Is Not Required in a Vaccine Strategy Against Genital Infection With Chlamydia trachomatis.

The requirement for vaccine-induced tissue-resident immunity for protection against one or repeated infections with Chlamydia trachomatis (C.t.) is still not fully resolved. In this study, our aim was to investigate to which degree tissue-resident Th1/Th17 T cells in the genital tract (GT) could add to the protection mediated by circulating immunity. Out of several mucosal vaccine strategies, a strategy termed SIM (for simultaneous intrauterine and parenteral immunization with CAF01 adjuvanted CTH522), was superior in generating genital tract tissue-resident Th1/Th17 T cell immunity. This led to a faster and stronger local CD4 T cell response post infection, consisting of multifunctional IFNγ/TNFα-producing Th1 T cells and IFNγ/TNFα/IL-17-producing Th17 T cells, and a faster recruitment of innate immune cells. Post infection, SIM animals showed an additional significant reduction in bacterial levels compared to mice having received only a parenteral vaccine. Nevertheless, the parenteral strategy reduced bacterial levels by 75%, and interestingly, post infection, these mice generated their own vaccine-derived genital tract tissue-resident memory Th1/Th17 T cells, which upon a subsequent infection showed as fast an activation in the genital tract, as observed in SIM mice. Furthermore, in contrast to after the first infection, both groups of mice now showed a similar infection-induced boost in local vaginal IgA and IgG titers. Thus, vaccine-induced resident immunity, generated pre-infection, led to an advantage in the response against the first infection, but not the second infection, suggesting that a parenteral vaccine strategy is a suitable vaccine strategy against infections with Chlamydia trachomatis.

Parenteral vaccination protects against transcervical infection with Chlamydia trachomatis and generate tissue-resident T cells post-challenge.

The optimal protective immunity against Chlamydia trachomatis (C.t.) is still not fully resolved. One of the unresolved issues concerns the importance of resident immunity, since a recent study showed that optimal protection against a transcervical (TC) infection required genital tissue-resident memory T cells. An important question in the Chlamydia field is therefore if a parenteral vaccine strategy, inducing only circulating immunity primed at a nonmucosal site, should be pursued by Chlamydia vaccine developers. To address this question we studied the protective efficacy of a parenteral Chlamydia vaccine, formulated in the Th1/Th17 T cell-inducing adjuvant CAF01. We found that a parenteral vaccination induced significant protection against a TC infection and against development of chronic pathology. Protection correlated with rapid recruitment of Th1/Th17 T cells to the genital tract (GT), which efficiently prevented infection-driven generation of low quality Th1 or Th17 T cells, and instead maintained a pool of high quality multifunctional Th1/Th17 T cells in the GT throughout the infection. After clearance of the infection, a pool of these cells settled in the GT as tissue-resident Th1 and Th17 cells expressing CD69 but not CD103, CD49d, or CCR7, where they responded rapidly to a reinfection. These results show that a nonmucosal parenteral strategy inducing Th1 and Th17 T cells mediates protection against both infection with C.t. as well as development of chronic pathology, and lead to post-challenge protective tissue-resident memory immunity in the genital tract.