Bhlhe40 function in activated B and TFH cells restrains the GC reaction and prevents lymphomagenesis

The generation of high-affinity antibodies against pathogens and vaccines requires the germinal center (GC) reaction, which relies on a complex interplay between specialized effector B and CD4 T lymphocytes, the GC B cells and T follicular helper (T-FH) cells. Intriguingly, several positive key regulators of the GC reaction are common for both cell types. Here, we report that the transcription factor Bhlhe40 is a crucial cell-intrinsic negative regulator affecting both the B and T cell sides of the GC reaction. In activated CD4 T cells, Bhlhe40 was required to restrain proliferation, thus limiting the number of T-FH cells. In B cells, Bhlhe40 executed its function in the first days after immunization by selectively restricting the generation of the earliest GC B cells but not of early memory B cells or plasmablasts. Bhlhe40-deficient mice with progressing age succumbed to a B cell lymphoma characterized by the accumulation of monoclonal GC B-like cells and polyclonal T-FH cells in various tissues. The transcription factor Bhlhe40 restrains the germinal center reaction through cell-intrinsic functions in both activated B cells and T follicular helper cells. The absence of Bhlhe40 results in a dysregulated germinal center response and lymphomagenesis.

Automated summary

The transcription factor Bhlhe40 plays a crucial negative regulatory role in the germinal center reaction by affecting both B cells and T follicular helper cells intrinsically, leading to a dysregulated germinal center response and potential lymphomagenesis in its absence.