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c-Myb is required for plasma cell migration to bone marrow after immunization or infection.

Good-Jacobson KL, O'Donnell K, Belz GT, Nutt SL, Tarlinton DM - J. Exp. Med. (2015)

Bottom Line: Here, we detail the critical role of the transcription factor c-Myb in determining plasma cell location.This was correlated with a dramatic reduction of plasma cells in peripheral blood, mislocalization in spleen, and an inability of c-Myb-deficient plasma cells to migrate along a CXCL12 gradient.Therefore, c-Myb plays an essential, novel role in establishing the long-lived plasma cell population in the BM via responsiveness to chemokine migration cues.

View Article: PubMed Central - HTML - PubMed

Affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia jacobson@wehi.edu.au tarlinton@wehi.edu.au.

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B cell–intrinsic migratory defect. (A) Schematic representation of mixed BM chimera setup. BM from either Cd23Cre/+ (horizontal stripes) or c-Mybfl/flCd23Cre/+ (white bars) were mixed 1:1 with BM from Ly5.1 (black or gray) and injected into irradiated Ly5.1 recipient mice. Mice were rested for at least 7 wk, after which they were immunized with NP-KLH precipitated in alum. (B and C) NP+IgG1+ BM ASCs were assessed at 2 wk after immunization by sort-purification and ELISPOT analysis from 50:50 BM chimeras; n = 5 per genotype; results are representative of two independent experiments. (D and E) Cd23Cre/+ (black bars) and c-Mybfl/flCd23Cre/+ (white bars) mice were infected with HKx31 influenza. Flu-specific IgG+ ASCs were assessed in the spleen (D) and BM (E) 6 wk after infection (n = 5 per genotype). Results are representative of two independent experiments per time point. (F and H) Cd23Cre/+ (black bars) and c-Mybfl/flCd23Cre/+ (white bars) mice were immunized with NP-KLH precipitated in alum, rested for at least 4 wk, and then boosted with NP-KLH in PBS. At day 3–4 after boost, NP+IgG1+ ASCs were assessed in the BM (F) and peripheral blood (G-H). n ≥ 4 per genotype, representative of three independent experiments. Bar, 3 mm. *, P < 0.05; **, P < 0.01 (Mann-Whitney nonparametric, two-tailed test; mean ± SEM).
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fig2: B cell–intrinsic migratory defect. (A) Schematic representation of mixed BM chimera setup. BM from either Cd23Cre/+ (horizontal stripes) or c-Mybfl/flCd23Cre/+ (white bars) were mixed 1:1 with BM from Ly5.1 (black or gray) and injected into irradiated Ly5.1 recipient mice. Mice were rested for at least 7 wk, after which they were immunized with NP-KLH precipitated in alum. (B and C) NP+IgG1+ BM ASCs were assessed at 2 wk after immunization by sort-purification and ELISPOT analysis from 50:50 BM chimeras; n = 5 per genotype; results are representative of two independent experiments. (D and E) Cd23Cre/+ (black bars) and c-Mybfl/flCd23Cre/+ (white bars) mice were infected with HKx31 influenza. Flu-specific IgG+ ASCs were assessed in the spleen (D) and BM (E) 6 wk after infection (n = 5 per genotype). Results are representative of two independent experiments per time point. (F and H) Cd23Cre/+ (black bars) and c-Mybfl/flCd23Cre/+ (white bars) mice were immunized with NP-KLH precipitated in alum, rested for at least 4 wk, and then boosted with NP-KLH in PBS. At day 3–4 after boost, NP+IgG1+ ASCs were assessed in the BM (F) and peripheral blood (G-H). n ≥ 4 per genotype, representative of three independent experiments. Bar, 3 mm. *, P < 0.05; **, P < 0.01 (Mann-Whitney nonparametric, two-tailed test; mean ± SEM).

Mentions: To rule out potential secondary changes in the microenvironment affecting migration of ASCs in c-Mybfl/flCd23Cre/+ mice, mixed BM chimeras were created. Ly5.1 wild-type BM was mixed 1:1 with Ly5.2 c-Mybfl/flCd23Cre/+ (or Cd23Cre/+ only for control chimeras) and used to reconstitute irradiated recipients (Fig. 2 A). Immunization of these chimeras revealed Ly5.1+NP+IgG1+ ASCs were present in the BM (Fig. 2, B and C), as were Cd23Cre/+ Ly5.2+NP+IgG1+ ASCs (Fig. 2 C). In contrast, NP+IgG1+ c-Myb–deficient, BM-resident ASCs were absent (Fig. 2 B). Therefore, although wild-type ASCs migrated to the BM, c-Myb–deficient ASCs did not within the same animal, demonstrating the B cell intrinsic basis of the defect.


c-Myb is required for plasma cell migration to bone marrow after immunization or infection.

Good-Jacobson KL, O'Donnell K, Belz GT, Nutt SL, Tarlinton DM - J. Exp. Med. (2015)

B cell–intrinsic migratory defect. (A) Schematic representation of mixed BM chimera setup. BM from either Cd23Cre/+ (horizontal stripes) or c-Mybfl/flCd23Cre/+ (white bars) were mixed 1:1 with BM from Ly5.1 (black or gray) and injected into irradiated Ly5.1 recipient mice. Mice were rested for at least 7 wk, after which they were immunized with NP-KLH precipitated in alum. (B and C) NP+IgG1+ BM ASCs were assessed at 2 wk after immunization by sort-purification and ELISPOT analysis from 50:50 BM chimeras; n = 5 per genotype; results are representative of two independent experiments. (D and E) Cd23Cre/+ (black bars) and c-Mybfl/flCd23Cre/+ (white bars) mice were infected with HKx31 influenza. Flu-specific IgG+ ASCs were assessed in the spleen (D) and BM (E) 6 wk after infection (n = 5 per genotype). Results are representative of two independent experiments per time point. (F and H) Cd23Cre/+ (black bars) and c-Mybfl/flCd23Cre/+ (white bars) mice were immunized with NP-KLH precipitated in alum, rested for at least 4 wk, and then boosted with NP-KLH in PBS. At day 3–4 after boost, NP+IgG1+ ASCs were assessed in the BM (F) and peripheral blood (G-H). n ≥ 4 per genotype, representative of three independent experiments. Bar, 3 mm. *, P < 0.05; **, P < 0.01 (Mann-Whitney nonparametric, two-tailed test; mean ± SEM).
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fig2: B cell–intrinsic migratory defect. (A) Schematic representation of mixed BM chimera setup. BM from either Cd23Cre/+ (horizontal stripes) or c-Mybfl/flCd23Cre/+ (white bars) were mixed 1:1 with BM from Ly5.1 (black or gray) and injected into irradiated Ly5.1 recipient mice. Mice were rested for at least 7 wk, after which they were immunized with NP-KLH precipitated in alum. (B and C) NP+IgG1+ BM ASCs were assessed at 2 wk after immunization by sort-purification and ELISPOT analysis from 50:50 BM chimeras; n = 5 per genotype; results are representative of two independent experiments. (D and E) Cd23Cre/+ (black bars) and c-Mybfl/flCd23Cre/+ (white bars) mice were infected with HKx31 influenza. Flu-specific IgG+ ASCs were assessed in the spleen (D) and BM (E) 6 wk after infection (n = 5 per genotype). Results are representative of two independent experiments per time point. (F and H) Cd23Cre/+ (black bars) and c-Mybfl/flCd23Cre/+ (white bars) mice were immunized with NP-KLH precipitated in alum, rested for at least 4 wk, and then boosted with NP-KLH in PBS. At day 3–4 after boost, NP+IgG1+ ASCs were assessed in the BM (F) and peripheral blood (G-H). n ≥ 4 per genotype, representative of three independent experiments. Bar, 3 mm. *, P < 0.05; **, P < 0.01 (Mann-Whitney nonparametric, two-tailed test; mean ± SEM).
Mentions: To rule out potential secondary changes in the microenvironment affecting migration of ASCs in c-Mybfl/flCd23Cre/+ mice, mixed BM chimeras were created. Ly5.1 wild-type BM was mixed 1:1 with Ly5.2 c-Mybfl/flCd23Cre/+ (or Cd23Cre/+ only for control chimeras) and used to reconstitute irradiated recipients (Fig. 2 A). Immunization of these chimeras revealed Ly5.1+NP+IgG1+ ASCs were present in the BM (Fig. 2, B and C), as were Cd23Cre/+ Ly5.2+NP+IgG1+ ASCs (Fig. 2 C). In contrast, NP+IgG1+ c-Myb–deficient, BM-resident ASCs were absent (Fig. 2 B). Therefore, although wild-type ASCs migrated to the BM, c-Myb–deficient ASCs did not within the same animal, demonstrating the B cell intrinsic basis of the defect.

Bottom Line: Here, we detail the critical role of the transcription factor c-Myb in determining plasma cell location.This was correlated with a dramatic reduction of plasma cells in peripheral blood, mislocalization in spleen, and an inability of c-Myb-deficient plasma cells to migrate along a CXCL12 gradient.Therefore, c-Myb plays an essential, novel role in establishing the long-lived plasma cell population in the BM via responsiveness to chemokine migration cues.

View Article: PubMed Central - HTML - PubMed

Affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia jacobson@wehi.edu.au tarlinton@wehi.edu.au.

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Related in: MedlinePlus