Timothy A. Springer


Harvard Medical School
Boston Childrenís Hospital
3 Blackfan Circle, CLSB, Rm 3103
Boston, MA 02115
Tel: 617-713-8200
Fax: 617-713-8232
Email: timothy.springer@childrens.harvard.edu




We work on receptor-ligand interactions and signal transmission across membranes. Students find my lab fascinating because of the wide range of techniques we use to answer immunological questions, including cell culture, determination of structures of receptors and ligands, single-molecule work on receptor-ligand interactions, and biophysical studies of signal transduction across the plasma membrane. My laboratory has discovered and elucidated the mechanisms of action of many important adhesion molecules of the immune system, including integrins and ICAMs.

Two new projects on transforming growth factor beta (TGFβ) and malaria vaccine targets are taking my lab back to its immunological roots. Latent TGFβ, and receptors for active TGFβ are ubiquitous; it is activation of TGFβ in the extracellular space that limits immune responses, regulates Treg and Th17 cell development, differentiation of lymphocytes toward subsets specialized for mucosal environments such as intraepithelial lymphocytes, and IgA class switch, among others. However, we know nothing about how TGFβ is activated in the context of immune responses. Recently we have determined a structure of latent TGFβ that reveals how the latency associated protein (LAP), a 250 residue prodomain, shields the 110 residue growth factor, and participates in its activation. We have studied how a cell surface protein called GARP, which is selectively expressed on FOXP3+ Treg cells, becomes disulfide linked to latent TGFβ, and presents it for activation by integrins αvβ6 and αvβ8 that are expressed on immune cells, and bind to an RGD motif in LAP. We believe that yet another cell surface molecule that presents latent TGFβ remains to be discovered, and that cell-type expression of these molecules may regulate deviation to Treg or Th17 phenotypes. A wide range of projects, all the way from knockout mice to structure determination, are in the offing.

Two current types of malaria vaccines are directed either at achieving sterilizing prophylactic immunity against pre-erythrocytic forms (sporozoites and infected liver cells), or at preventing transmission. Transmission blocking vaccines to gametocyte surface antigens work when gametocytes emerge from ingested erythrocytes in the mosquito midgut, and are neutralized by antibodies taken up in the blood meal. We have recently determined a crystal structure of the sporozoite surface protein that is the immunogen in world-wide, phase III trials of vaccines for protecting infants against malaria. Its structure is surprising, and reveals a new feature that enables us to introduce mutations that should stabilize the sporozoite surface, rather than the shed form of the antigen, and greatly improve vaccines. Principles for how parasite surfaces are organized, and evade immune responses, are emerging. Exciting work is also ongoing on a molecule that mediates sporozoite gliding motility and host cell invasion, and on gametocyte surface molecules that have important functions including fusion between male and female gametes. Many immunological experiments are required to test the principles of how Malaria parasites evade immune responses, and to improve vaccines.

References:

Xie, C., J. Zhu, X. Chen, L. Mi, N. Nishida, and T.A. Springer. 2010. Structure of an integrin with an α I domain, complement receptor type 4.
EMBO J. 29:666-679.

Shi, M., Zhu, J., Wang, R., Chen, X., Mi, L., Walz, T., Springer, T.A. 2011. Latent TGF-β structure and activation.
Nature. In press.



Last Update: 1/6/2014