Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses during Plasmodium infection

Abstract

Summary Innate sensing mechanisms trigger a variety of humoral and cellular events that are essential to adaptive immune responses. Here we describe an innate sensing pathway triggered by Plasmodium infection that regulates dendritic cell (DC) homeostasis and adaptive immunity via Flt3L release. Plasmodium-induced Flt3L release requires toll-like receptor activation and type I interferon production. We find that type I interferon supports the up-regulation of xanthine dehydrogenase, which metabolizes the xanthine accumulating in infected erythrocytes to uric acid. Uric acid crystals trigger mast cells to release soluble Flt3L from a pre-synthesized membrane-associated precursor. During infection Flt3L preferentially stimulates expansion of the CD8α+/CD103+ DC subset or its BDCA3+ human DC equivalent and has a significant impact on the magnitude of T cell activation, mostly in the CD8+ compartment. Our findings highlight a new mechanism that regulates DC homeostasis and T cell responses to infection.

Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

“…Our results on CD8 + T cell activation confirm previous ex vivo data showing a superior efficiency of CD8 + DC at priming OT-I cells after exposure to transgenic PbA parasites expressing SIINFEKL (9). They are also consistent with in vivo studies showing a reduced number of activated endogenous CD8 + T cells after PbA infection of mice deficient in CD8 + DC (37,38,69). As CD8 + DC possess specialized machinery for cross-presentation (34), this likely underlies their unique capacity to prime CD8 + T cells during infection by Plasmodium species.…”

“…Also, depletion of CD8 + DC in PbAinfected mice resulted in a sharp decrease in the numbers of activated endogenous CD8 + T cells in the spleen, and CD4 + T cell activation was also impaired (37). A similar result was obtained when CD8 + DC were depleted in P. chabaudi-infected mice (38). Another study analyzing CD4 + T cell responses to P. chabaudi Ag showed CD8 + DC as superior to CD8 2 DC at MHC II presentation in the steady-state, but the latter were more efficient during infection (39).…”

“…The essential role for CD8 + DC in CD8 + T cell priming and their dominant role in CD4 + T cell priming puts this subset at the center of response initiation to blood-stage malaria parasites and suggests that strategies aimed at generating T cell responses against blood-stage malaria parasites will benefit from exploiting this DC subtype. The findings that individuals with severe disease in malaria endemic areas present with increased numbers of circulating BDCA3 + DC (96) (the human equivalent to mouse CD8 + DC) and activated CD8 + T cells (38) relative to those with mild malaria suggest that CD8 + T cell activation during blood-stage malaria may be driven by a similar process in humans as in the mouse model. More precise knowledge of the mechanisms that drive CD8 + DC function during malarial infections may thus allow us to develop more effective strategies to combat this disease.…”

Insufficient interleukin‐12 signalling favours differentiation of human CD4+ and CD8+ T cells into GATA‐3+ and GATA‐3+ T‐bet+ subsets in humanized mice

“…It has recently been reported that the treatment of humanized mice with the haematopoietic cytokine Flt3L leads to an increase in human BDCA-1 + and BDCA-3 + DC subsets 36,38 Both, BDCA-1 + and BDCA-3 + DC produce IL-12 after Flt3L expansion in humanized mice. 36 We treated HIS mice when human haematopoietic reconstitution had reached plateau levels (12 weeks post …”

Reduced naïve CD 8 + T ‐cell priming efficacy in elderly adults

“…This approach is based on an accelerated dendritic cell (DC) coculture system, designed for the optimal activation of antigen‐specific T‐cells from PBMCs (Martinuzzi et al ., 2011). As circulating human DCs are rare, DC precursors within the starting PBMC material were mobilized using FLT3 ligand (FLT3L) (Breton et al ., 2015), known for its capacity to enhance the induction of T‐cell responses (Guermonprez et al ., 2013), and matured with a standard cocktail of inflammatory cytokines (TNF, IL‐1β, PGE2, and IL‐7).Furthermore, we focused on the priming of CD8 + T‐cells specific for the melanoma antigen Melan‐A/MART‐1, restricted by HLA‐A*0201 (HLA‐A2 from hereon). This specificity is particularly amenable to in vitro studies with limited volume blood samples due to naturally high precursor frequencies in the naive pool and the widespread occurrrence of HLA‐A2 in the general population.…”