CD11c-Specific Deletion Reveals CREB as a Critical Regulator of DC Function during the Germinal Center Response

Abstract

Dendritic cells (DCs) are crucial for the balance between immune response and tolerance, but the molecular mechanism regulating development, differentiation, and homeostasis are poorly understood. The transcriptional activator CREB is involved in regulating different cells of the innate and adaptive immune system and is a transcriptional regulator of development, survival, activation, or proliferation in macrophages, dendritic cells, B cells, and T cells. To directly examine the role of CREB in the regulation of DCs, the CREB gene was targeted for deletion with a CD11c-cre transgene. The deletion of CREB in CD11c+ cells did not involve any developmental or systemic defects within DC populations. However, CREB deficiency in CD11c+ cells reduced germinal center (GC) B cells in steady state, and immunization with NP-CGG resulted in a reduced formation of GCs, paralleled by the reduced production of IgGs in sera of immunized mice. In conclusion, we demonstrate that CREB expression in CD11c+ cells enhances germinal center responses, most likely by altering DC function, which might have implications for autoimmune diseases that are associated with dysregulated GC responses.

CREB signals as PBMC-based biomarkers of cognitive dysfunction: A novel perspective of the brain-immune axis

“…CREB is thought to mediate interleukin 10 (IL-10) expression by macrophages (Ananieva et al, 2008) and DCs (Alvarez et al, 2009). Specific knockout of CREB in DCs leads to an impairment in immune processes related to DC function, specifically the expression of B cell lymphocytes in germinal centers (Ohl et al, 2018).…”

Dendritic cell ICAM-1 strengthens immune synapses but is dispensable for effector and memory responses

“…S1 and Materials and Methods). We chose the CD11c Cre to silence ICAM-1 expression, since it has been extensively used for targeting various genes in different DCs ( 35–37 ). The major DC subset involved in CD8 priming, namely cDC1, lost the majority of their ICAM-1 in CD11c-Cre:ICAM-1 fl/fl mice in both resting as well as skin vaccinated popliteal (skin-draining) LNs (Fig.…”

“…ICAM-1 on subcapsular macrophages may also modulate the efficiency of viral antigen spread inside infected LNs ( 32, 33 ), and B cell expressed ICAM-1 ( 34 ) may contribute to CD4 T cell differentiation. We have therefore constructed a new strain of ICAM-1 fl/fl mice and generated DC ICAM-1 knockout mice by crossing the ICAM-1 fl/fl strain with mice expressing the Cre recombinase under the DC enriched CD11c promoter ( 35–37 ). We used these mice to follow the specific contributions of DC ICAM-1 to CD8 priming and differentiation into effector and memory CD8 T cells in distinct vaccinated and virus-infected LNs ( 38, 39 ).…”

Phenotypic Characterization of Diffuse Large B-Cell Lymphoma Cells and Prognostic Impact

“…CD11c is also a marker of dendritic cells. It has been reported that CD11c-positive dendritic cells promote the formation of germinal centers in the steady state and their response after immunization [63]. Furthermore, it has been suggested that, in follicular lymphoma, the presence of CD11c-positive dendritic cells in the tumor micro-environment is involved in tumor progression or recurrence by supporting regulatory T-cell infiltration [64].…”