Inhibition of interleukin 7 receptor signaling by antigen receptor assembly.
After the productive rearrangement of immunoglobulin (Ig) heavy chain genes, precursor (pre-)B lymphocytes undergo a limited number of cell divisions in response to interleukin (IL)-7. Here, we present evidence that this phase of IL-7-dependent expansion is constrained by an inhibitory signal initiated by antigen receptor assembly. A line of pre-B cells from normal murine bone marrow that expresses a mu heavy chain with a D-proximal V(H)7183.2 region divides continuously in IL-7. IL-7 responsiveness ceases upon differentiation to the mu(1), kappa(1) stage, despite continuing expression of the IL-7 receptor (IL-7R), suggesting that antigen receptor assembly inhibits IL-7 responsiveness. This is confirmed by introduction of a rearranged lambda light chain gene, which inhibits proliferative signaling through the IL-7R. Inhibition is specific to the IL-7R, because it is overcome by replacement of the IL-7R cytoplasmic domain with corresponding sequences from the closely related IL-2Rbeta chain. Alteration of a single tyrosine residue, Tyr410, in the IL-7R cytoplasmic domain to phenylalanine also prevents the inhibition of proliferation after antigen receptor assembly. Thus, the loss of IL-7 responsiveness after antigen receptor assembly may be mediated through the recruitment of an inhibitory molecule to this residue. Our findings identify a novel mechanism that limits cytokine-dependent proliferation during B lymphopoiesis. This mechanism may be essential for the proper regulation of peripheral B lymphocyte numbers.
Smart
F M
FM
Wellcome Trust Centre for the Study of Molecular Mechanisms in Disease, and the Cancer Research Campaign Department of Oncology, University of Cambridge, The Cambridge Institute for Medical Research, Cambridge CB2 2XY, United Kingdom.
Venkitaraman
A R
AR
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002999:Clone Cells; D015322:Gene Rearrangement, B-Lymphocyte; D005803:Genes, Immunoglobulin; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D015851:Interleukin-7 / Q000494:pharmacology* / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000502:physiology; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D014162:Transfection
D007143:Immunoglobulin Heavy Chains; D015851:Interleukin-7; D019948:Receptors, Interleukin-4; D020395:Receptors, Interleukin-7; D011994:Recombinant Proteins