Notch2-dependent DC2s mediate splenic germinal center responses

Abstract

SignificanceHigh-affinity antibody responses involve selection of B cells in the germinal center (GC) by cognate interactions with T follicular helper (TFH) cells, which in turn must first be activated by classical dendritic cells (cDCs). We observe that Notch2-dependent cDC2s are required in vivo for induction of TFH cells, GC B cells, and specific antibody production in response to sheep red blood cell (SRBC) immunization. Notch2 signaling impacted a broad transcriptional program in cDC2s both at homeostasis and after SRBC immunization, although we have not identified a target gene that mediates TFH differentiation. Thus, Notch2 is a transcription factor that acts in cDCs and is selectively required for support of the GC reaction.

Phosphatase PTPN22 Regulates Dendritic Cell Homeostasis and cDC2 Dependent T Cell Responses

“…In the context of non-self cDC2-targeted antigen, Ptpn22 619W dependent expansion of cDC2 was sufficient to enhance T cell proliferation and T FH expansion following GC promoting SRBC stimulation (Figures 4F,G). Activation of ESAM + cDC2 is one of the earliest events in splenic GC formation leading to high-affinity antibody production (18,49). With aging, PTPN22 mutant mice develop many hallmarks of autoimmunity including increased effector T cells, activated B cells and higher immunoglobulin and autoantibody titres (33,43).…”

“…PTPN22 R620W is a risk allele associated with multiple autoantibody associated autoimmune diseases. Splenic cDC2 are essential initiators of T FH differentiation, leading to GC formation, and high-affinity antibody production (18,49). Interestingly, with age Ptpn22 −/− and Ptpn22 619W mice develop spontaneous GC, and enhanced serum IgG levels (33,43,50).…”

“…To evaluate cDC2 dependent antigen specific responses in vivo we administered 33D1-OVA conjugates to selectively target the cDC2 subset ( Supplementary Figure 4) (8). WT and Ptpn22 619W mice received CD45.1 OT-II CD4 + T cells and were immunized with 33D1-OVA in the presence of SRBCs to promote cDC2 activation ( Figure 4C), and potentiate OT-II proliferation and T FH responses (Figures 4D,E) (18,49). When compared to WT recipients, Ptpn22 619W cDC2 expansion was sufficient to enhance OT-II proliferation in vivo (Figure 4F).…”

Stem cell transplantation impairs dendritic cell trafficking and herpesvirus immunity

“…We found that mice with conditional KO of Notch2 in CD11c + cells do not develop splenomegaly (Supplemental Figure 1, C and D). Since lung cDC2s are required to induce T follicular helper cell (Tfh) differentiation in response to antigens (80) and support germinal center reactions (81), Notch2-dependent cDC2s are likely essential for both passing virus to B cells and subsequently stimulating germinal center reactions through Tfh cells. Note that MHV-68 infection can cause a considerable amount of B cells to express CD11c (82); thus, Notch2 in these B cells is knocked out in our experimental system.…”

Contribution of Dendritic Cells in Protective Immunity against Respiratory Syncytial Virus Infection

“…Unlike cDC1s, cDC2 subsets are considered to be responsible for the activation of CD4 + T cells by MHC-II-dependent antigen presentation [118]. Consequently, these subsets contribute to helper T cell polarization, including differentiation into Th2, Th17, and T follicular helper cells [10,102,[119][120][121]. These findings suggest the possibility that cDC2 populations support antibody-mediated protection.…”