Abstract
Cathepsin L (CTSL) is a ubiquitously expressed lysosomal cysteine peptidase with diverse and highly specific functions. The involvement of CTSL in thymic CD4+ T-cell positive selection has been well documented. Using CTSLnkt/nkt mice that lack CTSL activity, we have previously demonstrated that the absence of CTSL activity affects the homeostasis of the T-cell pool by decreasing CD4+ cell thymic production and increasing CD8+ thymocyte production. Herein we investigated the influence of CTSL activity on the homeostasis of peripheral B-cell populations and bone marrow (BM) B-cell maturation. B-cell numbers were increased in lymph nodes (LN), spleen and blood from CTSLnkt/nkt mice. Increases in splenic B-cell numbers were restricted to transitional T1 and T2 cells and to the marginal zone (MZ) cell subpopulation. No alterations in the proliferative or apoptosis levels were detected in peripheral B-cell populations from CTSLnkt/nkt mice. In the BM, the percentage and the absolute number of pre-pro-B, pro-B, pre-B, immature and mature B cells were not altered. However, in vitro and in vivo experiments showed that BM B-cell production was markedly increased in CTSLnkt/nkt mice. Besides, BM B-cell emigration to the spleen was increased in CTSLnkt/nkt mice. Colony-forming unit pre-B (CFU pre-B) assays in the presence of BM stromal cells (SC) and reciprocal BM chimeras revealed that both BM B-cell precursors and SC would contribute to sustain the increased B-cell hematopoiesis in CTSLnkt/nkt mice. Overall, our data clearly demonstrate that CTSL negatively regulates BM B-cell production and output therefore influencing the homeostasis of peripheral B cells.
Highlights
Both the percentage and absolute number of B220+CD19+lymph nodes (LN) cells were markedly increased in CTSLnkt/nkt mice (Fig 1B–C)
These mice showed increased percentage and absolute numbers of transitional (T1 and T2) splenic cells (Fig 8D– G). These results indicate that a B-cell precursor intrinsic alteration plays a role in the increase in bone marrow (BM) B-cell production and in the increase in transitional B-cell numbers observed in CTSLnkt/nkt mice
We have previously shown that the nkt mutation broadly affects the maturation and the homeostasis of T-cell populations
Summary
Once the Blineage restricted stage is reached, B-cell progenitors execute a programmed development, first rearranging the immunoglobulin heavy chain gene at the pro-B stage, undergoing multiple rounds of clonal expansion at the pre-B stage and rearranging the light chain gene to yield newly formed B cells expressing surface IgM. These immature B cells are exported primarily to the spleen where they progress through stages of immature transitional B cells and develop into mature naıve B cells [1]. A role for CTSL in the development and progression of cancer has been reported [16], [17]
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