Timothy A. Springer, Ph.D.

Timothy A. Springer, Ph.D.

Latham Family Professor, Professor of Biological Chemistry and Molecular Pharmacology, Professor of Medicine, Harvard Medical School
Program in Cellular and Moleculr Medicine, Division of Hematology/ Oncology, Department of Medicine, Boston Children's Hospital

Adhesion Receptors of the Immune System.

Adhesion molecules on lymphocytes and leukocytes regulate cell interactions in development, antigen recognition, homing, and inflammation.  Our work focuses on integrins, Ig superfamily cell adhesion molecules (CAM’s), and selectins.

Integrins are the most sophisticated adhesion molecules known.  Like many surface molecules, integrins can transmit signals into cells.  However, integrins also transmit "inside-out signals."  Other receptors transmit signals that impinge on the cytoplasmic and transmembrane domains of integrins.  In less than a second, these signals are transmitted to integrin extracellular domains, which undergo conformational movements that enable ligand binding.  Thus, integrins can rapidly stabilize contacts between lymphocytes and antigen-presenting cells, and between leukocytes in the bloodstream and endothelium at sites of inflammation. Integrins also mediate cell migration within the body, which involves highly regulated interactions with the actin cytoskeleton and extracellular ligands.

We are developing a three-dimensional picture of integrins and their ligands, to understand how they bind to one another, the moving parts of the integrin machines and how they are linked together, and the connections to other signaling molecules.

The lab also focuses on selectins and a4 integrins that have a unique function in the vasculature.  Their receptor-ligand interactions mediate rolling of leukocytes on endothelium, an adhesive modality that enables surveillance for signs of inflammation.  We are characterizing the molecular and cellular properties that enable such a transient form of adhesion under the high forces experienced by cells in blood vessels.

Whenever possible, we make connections between basic research and disease.  These include inherited defects of integrins in leukocyte adhesion deficiency, ICAM-1 as the cellular receptor for rhinovirus, and SDF-1 as the natural ligand for the HIV coreceptor CXCR4.  Our work may lead to clinical treatments for autoimmune and vascular diseases.

Selected Publications:

L., L., et al. Carbon nanotube-assisted optical activation of TGF-β signalling by near-infrared light. Nat Nanotechnol. 10, 5, 465-71 (2015).

Lin, F.-Y., Zhu, J., Eng, E.T., Hudson, N.E. & Springer, T.A. β-subunit Binding is Sufficient for Ligands to open the Integrin αIIbβ3 Headpiece. J Biol Chem. 291, 9, 4537-56 (2016).

Swearingen, K.E., et al. Interrogating the Plasmodium Sporozoite Surface: Identification of Surface-Exposed Proteins and Demonstration of Glycosylation on CSP and TRAP by Mass Spectrometry-Based Proteomics. PLoS Pathog 12, 4, e1005606 (2016).

Xu, S., Wang, J., Wang, J.-H. & Springer, T.A. Distinct recognition of complement iC3b by integrins αXβ2 and αMβ2. Proc Natl Acad Sci USA (2017).

Dong, X., et al. Force interacts with macromolecular structure in activation of TGF-β. Nature 542, 7639, 55-59 (2017).

Contact Information

Program in Cellular and Molecular Medicine
Center for Life Sciences Building
Boston Children's Hospital
3 Blackfan Circle, Room 3103
Boston, MA 02115
p: 617 713-8200

Faculty Alphabetical