CRTC2 Regulates Plasma Cell Metabolism and Survival to Maintain Humoral Immune Responses
- Author(s): Hong, Jason S
- Advisor(s): Teitell, Michael A
- et al.
The humoral immune response is mediated by antigen activated B cells that
have terminally differentiated into antibody secreting cells (ASCs). The ASC pool is
composed of short-lived plasma cells (SLPCs) and long-lived plasma cells (LLPCs) that
secrete antigen-specific antibodies to clear an infection and maintain long-term
protective antibody titers to prevent subsequent reinfections. SLPCs have generally
been viewed to be formed from T cell-independent immune responses and localized in
the spleen. LLPCs have been viewed to be formed from T cell-dependent immune
responses and localized in the bone marrow. However, regardless of the type of
stimulating antigen, ASCs of varying lifespans, both SLPCs and LLPCs are found in the
spleen and bone marrow. Currently, it remains unclear as to what factors and pathways
regulate PC longevity.
Our laboratory previously identified the CREB coactivator CRTC2 as a regulator
of ASC differentiation. DNA double strand breaks associated with class switch
recombination activates a signaling pathway in human germinal center (GC) B cells that
results in the phosphorylation and inactivation of CRTC2. Phosphorylated CRTC2 is relocalized
to the cytoplasm and CRTC2 target genes are down-regulated. Dysregulation
of CRTC2 activity through over-expression of a nucleus-localized and constitutively
active form of CRTC2 (CRTC2-AA) in human tonsillar B cells, prevented GC B cells
from exiting the GC reaction and inhibited ASC differentiation. However, it remained
unclear whether the function of CRTC2 in this in vitro differentiation system would be
recapitulated in vivo and whether CRTC2 played any other roles in an in vivo humoral
To evaluate these questions, we generated a transgenic (TG) mouse model
which expresses CRTC2-AA at all stages of B cell development. Using these TG mice,
we demonstrate that Crtc2 repression in PCs is an intrinsic requirement for PC
metabolic fitness. Sustained CRTC2 activity shortened the survival of splenic and bone
marrow PCs which resulted in the reduction of long-lived PCs and antibody deficits in
response to immunizations and acute viral infection. We further demonstrated that TG
PCs adopt characteristics associated with SLPCs which include reduced antibody
secretion, glycolysis, oxidative metabolism, and spare respiratory capacity.
Mechanistically, Crtc2 repression is necessary for the fidelity of PC gene expression
and mRNA alternative-splicing programs, with both programs altered in TG PCs.
Combined, our results show that Crtc2 repression in PCs must occur to support PC
metabolism and extend PC survival and lifespan during a humoral immune response.
We hypothesize that the level of Crtc2 repression in differentiated ASCs determines
metabolic fitness and ultimately PC survival and longevity in the bone marrow.