CD8α− Dendritic Cells Induce Antigen-Specific T Follicular Helper Cells Generating Efficient Humoral Immune Responses

Abstract

Recent studies on T follicular helper (Tfh) cells have significantly advanced our understanding of T cell-dependent B cell responses. However, little is known about the early stage of Tfh cell commitment by dendritic cells (DCs), particularly by the conventional CD8α(+) and CD8α(-) DC subsets. We show that CD8α(-) DCs localized at the interfollicular zone play a pivotal role in the induction of antigen-specific Tfh cells by upregulating the expression of Icosl and Ox40l through the non-canonical NF-κB signaling pathway. Tfh cells induced by CD8α(-) DCs function as true B cell helpers, resulting in significantly increased humoral immune responses against various human pathogenic antigens, including Yersinia pestis LcrV, HIV Gag, and hepatitis B surface antigen. Our findings uncover a mechanistic role of CD8α(-) DCs in the initiation of Tfh cell differentiation and thereby provide a rationale for investigating CD8α(-) DCs in enhancing antigen-specific humoral immune responses for improving vaccines and therapeutics.

IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection

“…Here, using non-lethal models, we similarly revealed that IFNAR1-signalling proceeding via cDCs, but not B- or T-cells, regulated the generation of Tfh and GC B-cell responses. Given that cDCs are critical for early Tfh differentiation and initiation of humoral immune responses [18,62,63], we propose that IFNAR1-signalling within splenic cDC regulates CD4 + T-cell proliferation, ICOS expression, and Th1 and Tfh differentiation.…”

Monocyte differentiation and antigen-presenting functions

“…The location of monocytes within the interfollicular region suggests that they may directly or indirectly contribute to B cell maturation and/or antibody production. Indeed, an elegant study by Chakarov and Fazilleau 128,129 demonstrated that, similarly to cDCs [130][131][132][133][134][135][136] , Toll-like receptor 9 (TLR9)-stimulated monocytes directly present antigen and induce the differentiation of T FH cells via IL-6 production. Another study using a high-dose antigen regimen suggested that in the absence of cDCs, LY6C + monocytes (along with B cells) induce T FH cell development 137 .…”

The non-canonical NF-κB pathway in immunity and inflammation

“…Similarly, patients with mutations in NFKB2, producing non-processable p100 mutants lacking C-terminal phosphorylation sites, have reduced numbers of B cells and T FH cells and develop common variable immunodeficiency 108,110,122,123 . The non-canonical NF-κB pathway is also required to induce ICOSL expression on the CD8 - subset of DCs, which contributes to the induction of T FH cells 124 . Therefore, the non-canonical NF-κB pathway facilitates GC reactions via multiple mechanisms, including the survival of naive and GC B cells and the generation of T FH cells (FIG.…”