Kei Haniuda

Type 2 conventional dendritic cells (cDC2s) are functionally and phenotypically heterogenous. Previous work in mice and humans identified two cDC2 subsets (cDC2As and cDC2Bs) and a monocytic DC3 subset. However, the microenvironmental cues governing their distinct differentiation pathways remain unclear. Here, we delineate mouse cDC2 lineage relationships and the sequential signals required for cDC2A maintenance. We show that cDC2s, arising from the CLEC9A⁺ cDC progenitor, encompass T-BET-expressing cDC2As and two cDC2B subsets distinguished by MGL2 expression, with monocytic DC3s exhibiting transcriptional overlap with Mgl2⁻ cDC2Bs. Among these subsets, T-BET⁺ cDC2As dominate the spleen where they require cell-intrinsic retinoic acid signaling to sustain their differentiation via Notch signals. Lymphotoxin-β receptor signaling on splenic cDC2s limits F-actin content retaining cDC2s at sites of retinol delivery. In summary, these data establish the developmental and transcriptional relationships between diverse cDC2 subsets and identify signals that regulate their prevalence in specific lymphoid tissues.

Type II conventional dendritic cells (cDC2) are functionally and phenotypically heterogenous. Previous work in mice and humans identified two cDC2 subsets (cDC2A and cDC2B) and a monocytic DC3 subset. However, the microenvironmental cues governing their distinct differentiation pathways remain unclear. Here we delineate murine cDC2 lineage relationships and the sequential signals required for cDC2A maintenance. We show that cDC2s, arising from the CLEC9A+ cDC progenitor, encompass T-bet-expressing cDC2A and two cDC2B subsets distinguished by MGL2 expression, with monocytic DC3 exhibiting transcriptional overlap with Mgl2– cDC2B. Among these subsets, T-bet+ cDC2A dominate the spleen where they require cell-intrinsic retinoic acid (RA) signaling to sustain their differentiation via Notch signals. Lymphotoxin beta receptor signaling on splenic cDC2s limits F-actin content retaining cDC2 at sites of retinol delivery. In summary, these data establish the developmental and transcriptional relationships between diverse cDC2 subsets and identify signals that regulate their prevalence in specific lymphoid tissues.

Although IgA ⁺ long-lived plasma cells (LLPCs) generated following mucosal viral infection provide durable protection against reinfection, little is known about their generation. Here, we show that oral RV infection induces gut-resident LLPCs that produce highly mutated protective IgA. Unlike RV-specific IgG ⁺ LLPCs, IgA ⁺ LLPCs were generated independently of MHCII expression by dendritic cells – rather MHCII expression by B cells was both necessary and sufficient. B cell MHCII was also sufficient to induce a unique population of T-bet ⁺ follicular helper T (T _FH 1) cells which were crucial for RV-specific IgA ⁺ LLPC accumulation in the gut via IFNγ- and CXCR3-dependent mechanisms. Similar to RV infection, T _FH 1 cells were required for influenza-specific IgA response. However, unlike RV infection, B cell MHCII was not sufficient to induce influenza-specific IgA ⁺ LLPCs, suggesting the operation of mucosal site-specific priming mechanisms. Collectively, our data reveal that unconventionally primed T _FH 1 cells support IgA responses to mucosal viral infections.

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis, often progressing to renal failure. IgAN is triggered by IgA deposition in the glomerular mesangium by an undefined mechanism. Here, we show that grouped ddY (gddY) mice, a spontaneous IgAN model, produce serum IgA against mesangial antigens, including βII-spectrin. Most patients with IgAN also have serum anti–βII-spectrin IgA. As in patients with IgAN, IgA ⁺ plasmablasts accumulate in the kidneys of gddY mice. IgA antibodies cloned from the plasmablasts carry substantial V-region mutations and bind to βII-spectrin and the surface of mesangial cells. These IgAs recognize transfected and endogenous βII-spectrin exposed on the surface of embryonic kidney–derived cells. Last, we demonstrate that the cloned IgA can bind selectively to glomerular mesangial regions in situ. The identification of IgA autoantibody and its antigen in IgAN provides key insights into disease onset and redefines IgAN as a tissue-specific autoimmune disease.

Antigens (Ags) with multivalent and repetitive structure elicit IgG production in a T cell-independent manner. However, the mechanisms by which such T cell-independent type-2 (TI-2) Ags induce IgG responses remain obscure. Here we report that BCR engagement with a TI-2 Ag but not with a T cell-dependent (TD) Ag was able to induce the transcription of activation-induced cytidine deaminase ( AID ) and efficient class switching to IgG3 upon co-stimulation with IL-1 or IFN-α. TI-2 Ags strongly induced the phosphorylation of protein kinase C (PKC)δ and PKCδ mediated the AID transcription through the induction of BATF, the key transcriptional regulator of AID expression. In PKCδ-deficient mice, production of IgG was intact against TD Ag but abrogated against typical TI-2 Ags as well as commensal bacteria, and experimental disruption of the gut epithelial barrier resulted in fatal bacteremia. Thus, our results revealed novel molecular requirements for class-switching in the TI-2 response and highlighted its importance in homeostatic commensal-specific IgG production.