David Michael Allman, Ph.D.
3620 Hamilton Walk
Philadelphia, PA 19104-6082
Fax: (215) 573-2350
Pennsylvania State University, 1982.
University of Pennsylvania, 1993.
Description of Research ExpertiseResearch Interests:
Plasma cell differentiation, B cell development
Our main focus concerns the mechanisms underlying differentiation within the B cell lineage. We are currently focusing on two aspects of B cell development and differentiation.
1) A central interest in my lab concerns the differentiation of antibody-secreting plasma cells from naïve and memory B cells. We are primarily interested in the following questions: a) How long to plasma cells live and what signals regulate their survival? b) Do plasma cells located at sites other than the bone marrow, such as within the gut mucosa, utilize the same survival mechanisms as those in the marrow? c) To what extent does persisting antigen or chronic infection promote lasting antibody responses? d) What are the regulatory networks, transcriptional and otherwise, that underwrite the differentiation of an activated B cell into an antibody-secreting plasma cell?
Background: High-affinity neutralizing antibodies play central roles if combating infections and constitute the chief mechanism underlying the vast majority of effective vaccines. Once induced, antigen-specific antibodies can be found in the serum long after infection or vaccination. A key question in immunology is how this works: Are lasting antibody responses mediated by memory B cells, induced periodically to generate short-lived plasma cells by persisting antigen? Or does the durability of serum antibody titers reflect the activity of long-lived plasma cells?
It is generally accepted that, once generated in peripheral lymphoid tissues, some new plasma cells home to the bone marrow where they survive for months to years in mice, and perhaps decades in people. However, the vast majority of newly generated plasma cells fail to become long-lived. Given that certain vaccines fail to induce long-term protective immunity, it follows that these antigens or immunization strategies fail to induce the formation of long-lived plasma cells. We would like to understand why.
To this end, we are striving to understand the factors underlying plasma cell lifespans, and why some plasma cells become long-lived, while others do not. We are examining this issue on both the cellular and molecular levels. With a cellular perspective, we have developed strategies to identify newly formed versus long-lived plasma cells in the bone marrow. This capacity also allows us to evaluate different types of antigens and immunization strategies for their capacity to induce short- and long-lived plasma cells. From these experiments we have learned that the bone marrow plasma cell pool is exceptionally dynamic, containing large fractions of newly formed plasma cells that must compete effectively for presumably limiting survival niches. Hence we are working to define the components of these niches and determine how to manipulate them. For a molecular perspective, we have also developed genome-wide gene expression data sets for short- and long-lived plasma cells in the bone marrow and in the gut mucosa. These data that have inspired new hypotheses about the biochemical and transcriptional pathways underlying adoption of the plasma cell fate by naïve B cells and the role of mitosis in this process.
In related work, we are focused on elucidating the influence of microbe-lymphocyte interactions in the gastrointestinal tract on systemic immunity, particularly the generation and maintenance of serum IgA responses.
2) The second main focus in my laboratory concerns how specific transcription factors promote the earliest phases of B cell development from multipotent progenitors.
Background: To generate early B-lineage cells, the development of alternative lineages such as T cells, innate lymphoid cells, and myeloid lineage cells must be suppressed. Previous work on this question concentrated 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. Recent work in the lab has shown that EBF accomplishes this task by actively and directly repressing the T cell and innate lymphoid cell-requisite transcription factor Gata3. To test this hypothesis further we developed synthetic Zinc-finger proteins to perturb interactions between EBF and discrete cis elements in the Gata3 locus, and test the impact of these perturbations on early B and T cell development. The latter studies revealed a general strategy for perturbing interactions between known transcription factors and relevant regulatory cis elements in a wide variety of experimental systems; we are applying this general approach to several differentiation pathways including early plasma cell differentiation.
Some recent peer-reviewed papers:
1. Banerjee, A., D. Northrup, H. Boukarabila, S. E. Jacobsen, and D. Allman. 2013. Transcriptional repression of Gata3 is essential for early B cell commitment. Immunity 38: 930-942.
2. Bortnick, A., and D. Allman. 2013. What is and what should always have been: long-lived plasma cells induced by T cell-independent antigens. J Immunol 190: 5913-5918.
3. Bortnick, A., I. Chernova, W. J. Quinn, 3rd, M. Mugnier, M. P. Cancro, and D. Allman. 2012. Long-lived bone marrow plasma cells are induced early in response to T cell-independent or T cell-dependent antigens. J Immunol 188: 5389-5396.
4. Calamito, M., M. M. Juntilla, M. Thomas, D. L. Northrup, J. Rathmell, M. J. Birnbaum, G. Koretzky, and D. Allman. 2010. Akt1 and Akt2 promote peripheral B-cell maturation and survival. Blood 115: 4043-4050.
5. Pongubala, J. M., D. L. Northrup, D. W. Lancki, K. L. Medina, T. Treiber, E. Bertolino, M. Thomas, R. Grosschedl, D. Allman, and H. Singh. 2008. Transcription factor EBF restricts alternative lineage options and promotes B cell fate commitment independently of Pax5. Nat Immunol 9:203-215.
6. Lindsley, R. C., M. Thomas, B. Srivastava, and D. Allman. 2007. Generation of peripheral B cells occurs via two spatially and temporally distinct pathways. Blood 109:2521-2528.
Selected PublicationsHarman BC, Northrup DL, Allman D: Resolution of unique Sca-1highc-Kit- lymphoid-biased progenitors in adult bone marrow. J Immunol. 181(11): 7514-7524, December 2008.
Pongubala JM, Northrup DL, Lancki DW, Medina KL, Treiber T, Bertolino E, Thomas M, Grosschedl R, **Allman D, **Singh H : Transcription factor EBF restricts alternative lineage options and promotes B cell fate commitment independently of Pax5. Nature Immunol. 9(2): 203-215, February 2008 Notes: ** Shared senior authorship
Lindsley RC, Thomas M, Srivastava B, Allman D: Generation of peripheral B cells occurs via two spatially and temporally distinct pathways. Blood 109(6): 2521-8, March 2007 Notes: Epub 2006 Nov 14.
Thomas M, Calamito M, Srivastava B, Maillard I, Pear WS, Allman D : Notch activity synergizes with B cell receptor and CD40 signaling to enhance B cell activation. Blood 109(8): 3342-50, April 2007 Notes: Epub 2006 Dec 19.
Allman D, Dalod M, Asselin-Paturel C, Delale T, Robbins SH, Trinchieri G, Biron CA, Kastner P, Chan S: Ikaros is required for plasmacytoid dendritic cell differentiation. Blood 108(13): 4025-34, Dec 2006 Notes: Epub 2006 Aug 15.
Harman BC, Miller JP, Nikbakht N, Gerstein R, Allman D: Mouse plasmacytoid dendritic cells derive exclusively from estrogen-resistant myeloid progenitors. Blood 108(3): 878, Feb 2006.
Srivastava B, Quinn 3rd WJ, Hazard K, Erikson J, Allman D: Characterization of marginal zone B cell precursors. J Exp Med. 202(9): 1225-34, November 2005.
Allman D, Sambandam A, Kim S, Miller JP, Pagan A, Well D, Meraz A, Bhandoola A: Thymopoiesis independent of common lymphoid progenitors. Nat Immunol. 4(2): 168-174, February 2003.
Miller JP, Allman D: The decline in B lymphopoiesis in aged mice reflects loss of very early B-lineage precursors. J Immunol. 171(5): 2326-2330, September 2003.
Miller JP, Izon D, DeMuth W, Gerstein R, Bhandoola A, Allman D: The earliest step in B-lineage differentiation from common lymphoid progenitors is critically dependent upon interleukin-7. J Exp Med. 196(5): 705-711, September 2002.