Description of Research Expertise

Research Interests:

Early B cell development and peripheral B cell differentiation

Research Summary

In my laboratory we aim to understand the mechanisms whereby stem cells, or more specifically multipotent hematopoietic progenitors, commit to the B cell lineage. In addition, we are working to understand how and why newly formed B cells are influenced to generate specific B cell subtypes with unique functions, and to understand how aging negatively impacts each of these processes. We address these and related questions by integrating a combination of experimental approaches including multiparameter flow cytometry and high speed cell sorting, mouse genetics (transgenics and knockouts), retroviral transduction of defined cell populations, and in vitro and in vivo assays to evaluate the impact of these genetic manipulations on B cell fate decisions.

One current area of investigation involves understanding how specific transcription factors promote the B cell fate. Previous work on this question focused heavily on the transcription factor Pax5 and its capacity to both promote B cell differentiation and inhibit alternative fates. However we recently showed that Early B cell Factor-1 (EBF), another transcription factor required for early B lymphopoiesis, both promotes B cell development and represses myeloid and T-lineage development independently of Pax5. These observations suggest that EBF and Pax5 work in parallel to promote the B cell fate by regulating the expression of non-overlapping target genes. We further suggest that many functions attributed to Pax5 may require EBF, as recent data show that Pax5 up-regulates EBF expression.

We are also working to understand the impact of aging on lymphocyte development. It is well appreciated that aging has a dramatic impact on hematopoiesis, leading to decreased B and T cell development and increased representation of myeloid lineage cells in the bone marrow. We previously showed that aging affects the generation of very early lymphoid progenitors. Indeed, we found that early B cell progenitors and lymphoid-biased progenitors in the bone marrow begin to decline even in middle-aged mice. Moreover, we found that the age-related loss of lymphoid progenitors becomes more severe in aged mice, and in many elderly mice (20-22 months or older) all lymphoid-biased progenitor pools fall below the level of detection. Currently we are focusing on the impact of aging on the earliest definable lymphoid progenitors in the bone marrow. A major aim of this work is to understand the cellular and molecular basis for the age-related loss of very early lymphoid progenitors with an emphasis on factors that may affect B cell genesis specifically. In this regard, we are currently testing the hypothesis that age-related loss of early B cell precursors reflects the dysfunction of EBF and related transcription factors.

As newly formed B cells exit the bone marrow they are subjected to several selection mechanisms that serve collectively to select against self-reactive cells and select for useful cells. We are particularly interested in the cellular and molecular mechanisms responsible for generating and maintaining marginal zone (MZ) B cells. MZ B cells are a unique B cell subpopulation that plays a critical role in host-defense against blood-borne pathogens. Our past work in this area includes studies identifying direct precursors for MZ B cells, as well as earlier work identifying more distant precursors for all peripheral B cells known as immature or transitional B cells. Currently we are working to understand the role of the B cell receptor (BCR) and additional cell surface receptors in MZ B cell development and maintenance. In this regard we showed that the BCR synergizes with the Notch receptor family to enhance B cell activation. Because Notch signaling is also required for MZ B cell development, we are now developing and testing models to test the hypothesis that BCR and Notch signals collaborate to guide immature B cells into the MZ B cell sublineage.

Finally, a recent objective in my laboratory is to understand the early extracellular cues that promote the differentiation of naïve B cells into antibody secreting plasma cells. In particular we wish to understand how such signals drive several unique features of plasma cells including resistance to radiation-induced apoptosis. Unlike all other resting B cell populations, plasma cells fail to undergo apoptosis after induction of double-stranded DNA breaks upon exposure to ionizing radiation. Malignant transformation of plasma cells results in multiple myeloma. Significantly, myeloma cells are resistant to radiation-based therapies, and are also able to sustain multiple successive translocations. Together these observations suggest that myeloma cells and normal plasma cells are uniquely resistant to molecular pathways that normally operate to kill cells that have suffered significant DNA damage. Accordingly, we are working to understand the extracellular and intracellular signals responsible for plasma cell resistance to such signals.

Recent Reviews:

1. Allman, D., and S. Pillai. 2008. Peripheral B cell subsets. Curr Opin Immunol 20:149-157.
2. Srivastava, B., R. C. Lindsley, N. Nikbakht, and D. Allman. 2005. Models for peripheral B cell development and homeostasis. Semin Immunol 17:175-182.
3. Allman, D., and J. P. Miller. 2005. The aging of early B-cell precursors. Immunol Rev 205:18-29.
4. Allman, D., B. Srivastava, and R. C. Lindsley. 2004. Alternative routes to maturity: branch points and pathways for generating follicular and marginal zone B cells. Immunol Rev 197:147-160.