Formation of B-1 B cells from neonatal B-1 transitional cells exhibits NF-κB redundancy - PubMed (original) (raw)

Formation of B-1 B cells from neonatal B-1 transitional cells exhibits NF-κB redundancy

Encarnacion Montecino-Rodriguez et al. J Immunol. 2011.

Abstract

The stages of development leading up to the formation of mature B-1 cells have not been identified. As a result, there is no basis for understanding why various genetic defects, and those in the classical or alternative NF-κB pathways in particular, differentially affect the B-1 and B-2 B cell lineages. In this article, we demonstrate that B-1 B cells are generated from transitional cell intermediates that emerge in a distinct neonatal wave of development that is sustained for ~2 wk after birth and then declines as B-2 transitional cells predominate. We further show that, in contrast to the dependence of B-2 transitional cells on the alternative pathway, the survival of neonatal B-1 transitional cells and their maturation into B-1 B cells occurs as long as either alternative or classical NF-κB signaling is intact. On the basis of these results, we have generated a model of B-1 development that allows the defects in B-1 and B-2 cell production observed in various NF-κB-deficient strains of mice to be placed into a coherent cellular context.

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Figures

FIGURE 1

FIGURE 1

Most sIgM+ B cells in neonatal SPL are immature transitional cells. A, Representative FACS analyses showing T1 and T2/T3 transitional, follicular (FO), marginal zone (MZ), and B-1 cells in the spleen (SPL) of 6 week and 5 day old SW mice. B, Age related changes in the relative frequency of B cell populations within sIgM+ cells in SPL. T1 and FO cells were defined according to their levels of sIgM and CD21 expression as illustrated in Supplementary Fig. 1 (on line). C, Representative FACS analyses of B-2, B-1a and B-1b cells in the peritoneal cavity (PerC) of 6 week and 5 day old SW mice. D, Age related changes in the relative frequency of B cell populations within sIgM+ cells in the PerC. n indicates the number of animals processed at the indicated time points. Average frequency and s.d. values for older animals are provided in Supplementary Table I (on line).

FIGURE 2

FIGURE 2

Neonatal T1 and T2/T3 cells preferentially mature into B-1 cells. A, Immunoglobulin Variable Heavy chain 11 (VH11) usage in T1, T2/T3 and FO cells isolated from 5 day and 8 week old SW mice. Representative FACS analyses of PerC cells from SCID mice transplanted with T1 and T2/T3 SPL cells isolated from 4 day (B) and 8 week old (C) donors. Plots show populations gated on donor sIgMa+ sIgDa+ cells.

FIGURE 3

FIGURE 3

Age related changes in the B-1 potential of T1 and T2/T3 neonatal SPL cells. A, Relative frequency of B-1 and B-2 cells within donor sIgMa+ cells in the PerC of SCID mice transplanted with T1 and T2/T3 transitional cells isolated from the SPL of 5 and 12 days and 6 week old SW mice. B, Relative frequencies of B-1a and B-1b cells within the donor B-1 cells shown in panel (A). Note that neonatal transitional cells generate B-1a cells more efficiently than adult transitional cells. Differences in reconstitution between adult and neonatal populations were tested by two-tailed unpaired Student's t test (a=0.05), P values are indicated in parentheses. n indicates the number of animal tested at each time point. n indicates the number of recipients processed in each group.

FIGURE 4

FIGURE 4

Distribution of B-1a, B-1b and B-2 cells in the PerC of adult BAFF-R–/–, XID and NF-κB1–/–Mice. Representative FACS analyses and relative frequency of B-1a, B-1b and B-2 cells in the PerC of BAFF-R—/— (A), XID (B) and NF-κB1—/— (C) mice are shown. n indicates the number of animals processed in each group.

FIGURE 5

FIGURE 5

Neonatal B-1 Transitional Cells Emerge in BAFF-R—/—, XID and NF-kB1—/— Mice. Age related changes in the relative frequency of B cell populations within sIgM+ cells in the SPL of adult (A) and neonatal (B) BAFF-R—/— mice, adult (C) and neonatal (D) XID mice and adult (E) and neonatal (F) NF-kkB1—/—mice. n indicates the number of animals processed in each group. Average frequency and s.d. values for older animals are provided in Supplementary Table II (on line).

FIGURE 6

FIGURE 6

B-1 Transitional Cells From BAFF-R—/— and NF-κB1—/— Mice Mature into B-1 cells. A, Representative FACS analyses of the PerC cells from RAG-2/SJL mice transplanted with T1 and T2/T3 SPL cells from 5 day and 8 week old BAFF-R—/— donors. B, Relative frequency of B-1 and B-2 cells within donor CD45.2+ sIgM+ cells in the PerC of recipients of BAFF-R–/– transitional cells from 5 day (Neonates) and 8 week (Adults) old donors. C, Representative FACS analyses of the PerC cells from RAG-2/SJL mice transplanted with T1 and T2/T3 SPL cells from 7 day old NF-κB1—/— donors. D, B-1 and B-2 potential of 7 day old NF-kB1—/— T1 and T2/T3 SPL cells. The upper panel shows the frequency of B-1 and B-2 cells reconstituted and the lower panel shows the frequency of B-1a and B-1b cells within the B-1 populations in the upper panels. The data in all panels represent relative frequencies within donor CD45.2+ sIgM+ cells. n indicates the number of recipients processed in each group.

FIGURE 7

FIGURE 7

Model of layered B-1 and B-2 development. In a first neonatal wave, B-1 CLPs generate B-1 progenitors that in turn differentiate into immature B-1 cells. The latter cells then migrate to the SPL where they mature into B-1a and B-1b cells through B-1 transitional cell intermediates. In a second wave, B-2 CLPs generate immature B-2 cells that mature into B-2 transitional cells in the SPL. This B-2 transitional cell wave becomes predominant in the adult. Emergence of B-1 and B-2 transitional cells is blocked when both the classical and alternative NF-κB pathways are inactivated (Step 1). However, selective defects in one or the other pathway have differential effects on the formation of mature B-1 and B-2 cells. While the survival and maturation of B-2 transitional cells is dependent on alternative NF-κB signaling (step 2), B-1 transitional cells emerge and mature in the absence of these signals. The number of mature B-1 cells is reduced in mice with defects in classical NF-κB signaling. However, this does not compromise the emergence or maturation of B-1 transitional cells into B-1a or B-1b cells. Instead, classical signaling is required for maintenance of the mature B-1 pool, and for B-1a cells in particular, following their formation (step 3).

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