Selective inhibition of class switching to IgG and IgE by recruitment of the HoxC4 and Oct-1 homeodomain proteins and Ku70/Ku86 to newly identified ATTT cis-elements

Immunoglobulin (Ig) class switching is central to the maturation of the antibody response as IgG, IgA, and IgE are endowed with more diverse biological effector functions than IgM. It is induced upon engagement of CD40 on B lymphocytes by CD40L expressed by activated CD4⁺ T cells and exposure of B cells to T cell-secreted cytokines including interleukin-4 and transforming growth factor-β. It begins with germ line I_H-C_H transcription and unfolds through class switch DNA recombination (CSR). We show here that the HoxC4 and Oct-1 homeodomain proteins together with the Ku70/Ku86 heterodimer bind as a complex to newly identified switch (S) regulatory ATTT elements (SREs) in the Iγ and Iε promoters and downstream regions to dampen basal germ line Iγ-Cγ and Iε-Cε transcriptions and repress CSR to Cγ and Cε. This mechanism is inactive in the Cα1/Cα2 loci because of the lack of SREs in the Iα1/Iα2 promoters. Accordingly, in resting human IgM⁺IgD⁺ B cells, HoxC4, Oct-1, and Ku70/Ku86 can be readily identified as bound to the Iγ and Iε promoters but not the Iα1/Iα2 promoters. CD40 signaling dissociates the HoxC4·Oct-1·Ku complex from the Iγ and Iε promoter SREs, thereby relieving the I_H-C_H transcriptional repression and allowing CSR to unfold. Dissociation of HoxC4·Oct-1·Ku from DNA is hampered by CD153 engagement, a CD40-signaling inhibitor. Thus, these findings outline a HoxC4·Oct-1·Ku-dependent mechanism of selective regulation of class switching to IgG and IgE and further suggest distinct co-evolution and shared CSR activation pathways in the Cγ and Cε as opposed to the Cα1/Cα2 loci.