Transient IL-7/IL-7R signaling provides a mechanism for feedback inhibition of immunoglobulin heavy chain gene rearrangements.
Production of immunoglobulin heavy chain (IgH) protein feeds back to terminate further V(H) gene recombination, a phenomenon also referred to as allelic exclusion. Here we provide evidence to support the proposition that allelic exclusion is the consequence of terminating signals that activate V(H) genes for recombination. For the largest V(H)J558 family of genes, this occurs by attenuating IL-7/IL-7R signals in pre-B cells. Loss of these signals reverts the V(H) locus to a chromatin state that is associated with hypoacetylated histones and is less accessible to nucleases. Furthermore, hyperacetylation and accessibility of unrearranged V(H) genes can be restored in allelically excluded splenic B cells by activating this pathway. Thus, transient signals mediate V(H) gene activation and inactivation during development.
Chowdhury
Dipanjan
D
Department of Biology, Brandeis University, Waltham, MA 02454, USA.
Sen
Ranjan
R
D000107:Acetylation; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002460:Cell Line; D005246:Feedback; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006657:Histones / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D020395:Receptors, Interleukin-7 / Q000378:metabolism*; D015398:Signal Transduction
D006657:Histones; D015851:Interleukin-7; D020395:Receptors, Interleukin-7