A fine balance between life and death ensures that appropriate numbers of T and B cells are produced and maintained in the periphery. One regulator of this balance is the cytokine interleukin-7 (IL-7), which promotes the survival of lymphocytes. Stanley Korsmeyer and colleagues have now identified the BCL-2-family member myeloid-cell leukaemia 1 (MCL1) as a crucial component of the signalling pathway downstream of IL-7.
Mcl1 deficiency is embryonic lethal, so these studies involved a conditional deletion strategy (Cre–loxP). Mice with a conditional T-lineage deletion of Mcl1 had decreased numbers of peripheral CD4+ and CD8+ T cells. Similarly, B-lineage deletion markedly reduced the number of splenic and lymph-node B cells. The authors then looked at the specific developmental stage that is blocked in each case. T-lineage Mcl1-deficient mice had a reduced number of single-positive and double-positive thymocytes. The block was shown to occur earlier in the double-negative (DN) subset at the DN2 to DN3 transition, and the DN2 population had an increased number of apoptotic cells. For Mcl1 deficiency in the B-cell lineage, both pro-B- and pre-B-cell populations were reduced in the bone marrow, and increased apoptosis was observed in the pro-B-cell subset.
Interestingly, both pro-B-cell and DN2 populations are known to require cytokine survival signals and the developmental blocks observed in the Mcl1-deficient mice are similar to those seen for IL-7- or IL-7 receptor-deficient mice. Moreover, in vitro culture of DN1 and DN2 thymocytes with IL-7 resulted in an increase in Mcl1 messenger RNA and protein levels. So, what is the role of MCL1 in IL-7 signalling? Of the two pro-apoptotic BH3-only BCL-2-family proteins (BIM and BAD) that are affected by cytokine-dependent survival pathways, MCL1 interacted strongly with BIM. Therefore, MCL1 might function to prevent apoptosis of developing lymphocytes by binding BIM and preventing BIM-mediated activation of the pro-apoptotic proteins BAX and BAK.
This developmental model was confirmed for the maintenance of peripheral lymphocytes. The total deficiency of Mcl1 in adult mice led to depletion of T and B cells from the spleen, and adoptive-transfer experiments showed that the requirement for Mcl1 is intrinsic to T and B cells. In vitro, the IL-7-mediated survival of mature T cells required Mcl1. So, these studies have indicated conservation of cytokine-dependent survival pathways for the development and maintenance of both T and B cells.
ORIGINAL RESEARCH PAPER
Opferman, J. T. et al. Development and maintenance of B and T lymphocytes requires anti-apoptotic MCL-1. Nature 426, 671–676 (2003)
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Minton, K. Shared survival signals. Nat Rev Immunol 4, 4 (2004). https://doi.org/10.1038/nri1288
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DOI: https://doi.org/10.1038/nri1288