Notch2-dependent DC2s mediate splenic germinal center responses

Area of Science:

• Immunology
• Cell Biology
• Microbiology

Background:

• T follicular helper (T_FH) cells are essential for germinal center (GC) reactions and robust humoral immunity.
• Dendritic cells (DCs) comprise diverse subsets that specialize in initiating distinct immune responses.
• The specific role of classical dendritic cell (cDC) subsets in driving humoral immunity remains largely undefined.

Purpose of the Study:

• To investigate the requirement of distinct classical dendritic cell (cDC) subsets in supporting T follicular helper (T_FH) cell and germinal center (GC) B cell responses.
• To elucidate the role of Notch2 signaling in the development and function of cDC subsets involved in humoral immunity.

Main Methods:

• Utilized genetic mouse models to selectively ablate specific cDC subsets (cDC1s, Notch2-dependent cDC2s, Klf4-dependent cDC2s).
• Assessed the impact of cDC subset ablation on splenic germinal center reactions following immunization with sheep red blood cells and inactivated *Listeria monocytogenes*.
• Analyzed T_FH cell and GC B cell populations, as well as T cell activation efficiency.

Main Results:

• Identified a critical requirement for *Notch2*-dependent cDC2s, but not *Batf3*-dependent cDC1s or *Klf4*-dependent cDC2s, in promoting T_FH and GC B cell formation.
• Demonstrated that this cDC2-mediated effect on humoral immunity is independent of *Il2ra*, *Stat4*, and *Havcr2*.
• Showed that Notch2 signaling during cDC2 development impairs their capacity for MHC class II-restricted antigen presentation, thereby limiting CD4 T cell activation strength.

Conclusions:

• The *Notch2*-dependent cDC2 subset plays a nonredundant role in supporting humoral immune responses.
• This specific cDC2 subset is essential for efficient T_FH cell differentiation and germinal center B cell maturation.
• Notch2 signaling influences cDC2 function in a manner that impacts their ability to initiate adaptive immune responses.