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-beta. It begins with germ line IH-CH 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 Igamma and Iepsilon promoters and downstream regions to dampen basal germ line Igamma-Cgamma and Iepsilon-Cepsilon transcriptions and repress CSR to Cgamma and Cepsilon. This mechanism is inactive in the Calpha1/Calpha2 loci because of the lack of SREs in the Ialpha1/Ialpha2 promoters. Accordingly, in resting human IgM+IgD+ B cells, HoxC4, Oct-1, and Ku70/Ku86 can be readily identified as bound to the Igamma and Iepsilon promoters but not the Ialpha1/Ialpha2 promoters. CD40 signaling dissociates the HoxC4.Oct-1. Ku complex from the Igamma and Iepsilon promoter SREs, thereby relieving the IH-CH 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 Cgamma and Cepsilon as opposed to the Calpha1/Calpha2 loci.
Schaffer
András
A
Division of Molecular Immunology, Department of Pathology and Laboratory Medicine, Joan and Sanford I. Weill Medical College, Cornell University, New York, New York 10021, USA.
Kim
Edmund C
EC
Wu
Xiaoping
X
Zan
Hong
H
Testoni
Lucia
L
Salamon
Szilvia
S
Cerutti
Andrea
A
Casali
Paolo
P
D034961:Antigens, Nuclear / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D051863:Host Cell Factor C1; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000502:physiology*; D007073:Immunoglobulin E / Q000235:genetics*; D007074:Immunoglobulin G / Q000235:genetics*; D007132:Immunoglobulin Isotypes / Q000235:genetics / Q000276:immunology; D000072200:Ku Autoantigen; D050811:Octamer Transcription Factor-1; D011401:Promoter Regions, Genetic; D011995:Recombination, Genetic; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism*
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C497692:HCFC1 protein, human; C098691:HOXC4 protein, human; D018398:Homeodomain Proteins; D051863:Host Cell Factor C1; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D014157:Transcription Factors; D007073:Immunoglobulin E; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen