Stephen Desiderio

Academic Titles: 
Professor Emeritus

733 N. Broadway
Baltimore, MD 21205

Research Interest: 
Mechanisms of Development in the Immune System

The laboratory is interested in molecular and genetic mechanisms responsible for development of the immune system. The generation of immunologic diversity provides a spectacular example of genomic plasticity in the form of V(D)J recombination. This process, which builds antigen receptor genes from discrete gene segments, shares mechanistic features with transposition and, as a potential source of DNA damage, is subject to tight control. One control mechanism, identified in this laboratory, restricts V(D)J recombination to a specific time in cell cycle through the periodic destruction of the V(D)J recombinase. Using a combination of genetics and biochemistry, we have defined this process in detail. By constructing specific knock-in mutant mice we have gone on to show that this mechanism protects against the development of lymphoid cancers and their associated chromosomal translocations. More recently we have begun to study how V(D)J recombination is controlled at the level of chromatin modification, which governs accessibility of particular loci to the recombinase. Some common childhood lymphoid cancers show evidence of aberrant V(D)J recombination, and in one type of malignancy, T-lymphoid acute lymphocytic leukemia, we have identified somatic mutations in the V(D)J recombinase. We now wish to learn the effects of these mutations on recombination activity and genomic stability.

Another important unsolved set of problems in development surrounds the generation of immune cells from blood-forming stem cells in the bone marrow. While we know a great deal about the transcriptional control networks that support cell fate decisions in the developing immune system, far less is known about the signals that are provided by surrounding cells – the stroma. We have found that hedgehog– a critical morphogenic signal – maintains stromal cells in a state that promotes the generation of immune cells from stem cells. When hedgehog signaling is switched off in stromal cells, their ability to support immune cell differentiation is greatly impaired. By understanding how hedgehog signaling in stromal cells promotes immune development we hope to be better able to manipulate human immune responses for future therapeutic uses.

We are also interested in how immune cells respond to environmental cues. Activation of immune cells requires a balance between benefit and risk, and is tightly regulated. Some signals activate immune cells while others block responsiveness – a process called anergy. These signaling mechanisms share common features, including activation of kinases, mobilization of calcium and combinatorial regulation of transcription. We have uncovered a novel way in which calcium is regulated in response to antigen receptor stimulation and are testing whether this mechanism contributes to the decision between activation and anergy.

Selected Publications:
Wagner CL, Hanumanthu VS, Talbot CC Jr, Abraham RS, Hamm D, Gable DL, Kanakry CG, Applegate CD, Siliciano J, Jackson JB, Desiderio S, Alder JK, Luznik L, Armanios M. (2018) Short telomere syndromes cause a primary T cell immunodeficiency. J Clin Invest. 2018 Dec 3;128(12):5222-5234.  [ link ]
Ward A, Kumari G, Sen R, Desiderio S. (2018) The RAG-2 Inhibitory Domain Gates Accessibility Of The V(D)J Recombinase To Chromatin. Mol Cell Biol. 2018 May 14. pii: MCB.00159-18.  [ link ]
Lu W, Dordai D, Huso D, Desiderio S. (2018) Smoothened signaling in the mouse osteoblastoid lineage is required for efficient B lymphopoiesis. Blood. 2018 Jan 18;131(3):323-327.  [ link ]
Bettridge J, Na CH, Pandey A, Desiderio S. (2017) H3K4me3 induces allosteric conformational changes in the DNA-binding and catalytic regions of the V(D)J recombinase. Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):1904-1909. [ link ]
Desiderio S. (2016) Pumping the breaks on B cell development. J Exp Med. 2016 Feb 8;213(2):140.  [ link ]
Cooper CL, Hardy RR, Reth M, Desiderio S. (2012) Non-cell-autonomous hedgehog signaling promotes murine B lymphopoiesis from hematopoietic progenitors. Blood 7;119(23):5438-48. [ link ]
Zhang L, Reynolds TL, Shan X, Desiderio S. (2011) Coupling of V(D)J recombination to the cell cycle suppresses genomic instability and lymphoid tumorigenesis. Immunity 34: 163-174. [ link ]
Desiderio S. (2010) Temporal and spatial regulatory functions of the V(D)J recombinase. Seminars in Immunology 22:362-369. [ link ]
Liu Y, Subrahmanyam R, Chakraborty T, Sen R, Desiderio S. (2007). A plant homeodomain in RAG-2 that binds hypermethylated lysine 4 of histone H3 is necessary for efficient antigen-receptor-gene rearrangement. Immunity. 27:561-71. [ link ]
Caraveo G, van Rossum DB, Patterson RL, Snyder SH, Desiderio S. (2006). Action of TFII-I outside the nucleus as an inhibitor of agonist-induced calcium entry. Science. 314:122-5. [ link ]