The laboratory is interested in the molecular and genetic mechanisms responsible for development of the immune system. Among the most spectacular examples of genomic plasticity are the processes that generate immunologic diversity, including V(D)J recombination. V(D)J recombination, 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, our group has 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 may govern accessibility of particular loci to the recombinase.
A related interest is 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 recently uncovered a novel way in which calcium is regulated in response to antigen receptor stimulation and are now testing whether this mechanism contributes to the decision between activation and anergy.
Yoo, J.-Y., Huso, D.L., Nathans, D. and Desiderio, S. (2002) Specific ablation of Stat3 distorts the pattern of Stat3-responsive gene expression and impairs recovery from endotoxic shock. Cell 108:331-344.
Ross, A.E., Vuica, M. and Desiderio, S. (2003) Overlapping signals for protein degradation and nuclear localization define a role for intrinsic RAG-2 nuclear uptake in dividing cells. Mol. Cell. Biol., 23:5308-5319.
Jiang, H., Ross, A.E. and Desiderio, S. (2004) Cell cycle-dependent accumulation in vivo of transposition-competent complexes between recombination signal ends and full-length RAG proteins. J. Biol. Chem. 279:8478-8486.
Jiang, H., Chang, F.-C., Ross, A.E., Lee, J., Nakayama, K., Nakayama, K. and Desiderio, S. (2005) Ubiquitylation of RAG-2 by SKP2-SCF links destruction of the V(D)J recombinase to the cell cycle. Molecular Cell, 18: 699-709.
Caraveo, G., van Rossum, D.B., Patterson, R.L., Snyder, S.H. and Desiderio, S. (2006) Action of TFII-I outside the nucleus as an inhibitor of agonist-induced calcium entry. Science. 314:122-5.