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Inhibition of interleukin 7 receptor signaling by antigen receptor assembly.

Smart FM, Venkitaraman AR - J. Exp. Med. (2000)

Bottom Line: This is confirmed by introduction of a rearranged lambda light chain gene, which inhibits proliferative signaling through the IL-7R.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT
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.

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(A) The sequence of the productive IgH rearrangement from the pre-B cell line. (B) The V region sequence, shaded grey in A, is aligned with the sequence of VH7183.2. The D segment (shaded black) and the J region (unshaded) are also marked in A.
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Figure 2: (A) The sequence of the productive IgH rearrangement from the pre-B cell line. (B) The V region sequence, shaded grey in A, is aligned with the sequence of VH7183.2. The D segment (shaded black) and the J region (unshaded) are also marked in A.

Mentions: In these cells, a productive IgH gene rearrangement results in the synthesis of membrane-inserted μ heavy chains (Fig. 1 A). We have sequenced this productive rearrangement (Fig. 2 A). It involves a VH gene segment from the VH7183 family located in the D-proximal region of the murine IgH locus. Comparison of the sequence with known members of the family reveals a precise match with VH7183.2 (Fig. 2 B; reference 25). In contrast, the IgL genes remain in the germline configuration 16.


Inhibition of interleukin 7 receptor signaling by antigen receptor assembly.

Smart FM, Venkitaraman AR - J. Exp. Med. (2000)

(A) The sequence of the productive IgH rearrangement from the pre-B cell line. (B) The V region sequence, shaded grey in A, is aligned with the sequence of VH7183.2. The D segment (shaded black) and the J region (unshaded) are also marked in A.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195828&req=5

Figure 2: (A) The sequence of the productive IgH rearrangement from the pre-B cell line. (B) The V region sequence, shaded grey in A, is aligned with the sequence of VH7183.2. The D segment (shaded black) and the J region (unshaded) are also marked in A.
Mentions: In these cells, a productive IgH gene rearrangement results in the synthesis of membrane-inserted μ heavy chains (Fig. 1 A). We have sequenced this productive rearrangement (Fig. 2 A). It involves a VH gene segment from the VH7183 family located in the D-proximal region of the murine IgH locus. Comparison of the sequence with known members of the family reveals a precise match with VH7183.2 (Fig. 2 B; reference 25). In contrast, the IgL genes remain in the germline configuration 16.

Bottom Line: This is confirmed by introduction of a rearranged lambda light chain gene, which inhibits proliferative signaling through the IL-7R.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT
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.

Show MeSH