Immune Disease Institute
Program in Cellular and Molecular Medicine
Department of Microbiology and Immunobiology
Harvard Medical School
Center for Life Science Boston
3 Blackfan Circle
Division of Immunology
The Winau lab studies diverse aspects of antigen presentation, a process pivotal for activation of T-lymphocytes. Winau and colleagues investigate three principal pillars of antigen presentation, including helper molecules of processing (saposins, e.g.), entire presentation pathways (cross-priming, NKT cell activation), and the biology of antigen presenting cells (dendritic cells, stellate cells).
Saposins are small proteins located in the lysosome that are involved in lipid metabolism. We demonstrated that saposin C is able to extract lipid antigens from intralysosomal membranes and additionally is capable of binding to CD1b. Thus, saposins facilitate loading of lipid antigens on CD1 molecules for the activation of CD1-restricted T cells, which play an important role in tuberculosis but also in other infectious diseases and pathological conditions. Moreover, saposins are involved in processing of apoptotic bodies. Currently our group investigates the precise mechanism as to how saposins mediate antigen delivery by disintegration of apoptotic vesicles. Since saposins are able to interact with lipid bilayers leading to membrane destruction, a recent project examines the possible antibiotic impact of saposins on bacterial cell walls.
NKT cells represent a lymphocyte subset implicated in immune regulation mainly through rapid burst of cytokines such as IFN-γ and IL-4, thereby imprinting downstream immune responses. They are associated with pathological conditions including cancer, autoimmunity, and infection. In addition to diverse exogenous ligands including alpha-galactosylceramide (α-GalCer), NKT cells react with the endogenous lipid antigen isoglobotrihexosylceramide (iGb3). Because antigenicity of iGb3 is comparable to the nominal antigen α-GalCer, we search for control mechanisms that avoid overstimulation of NKT cells. Our group investigates the regulated availability of the endogenous lipid antigen for NKT cells dependent on lysosomal α-galactosidase activity.
Hepatic stellate cells (or Ito cells) are star-shaped cells located in the liver, and they mediate a multitude of primarily non-immunological functions. They play an essential role in the metabolism of vitamin A and store 80% of total body retinol. Upon activation, stellate cells differentiate into myofibroblasts for production of extracellular matrix, leading to liver fibrosis. Recently, our group demonstrated that hepatic stellate cells perform potent antigen presentation stimulating NKT cells as well as conventional T-lymphocytes. Additionally, stellate cells induced protective immunity against bacterial infection. Currently, we establish in vivo models for stellate cell depletion in order to investigate the impact of stellate cells on T cell instruction and differentiation mediated by vitamin A-derived retinoic acid.
Schaible,U.E., Winau,F., Sieling,P.A., Fischer,K., Collins,H.L., Hagens,K., Modlin,R.L., Brinkmann,V., and Kaufmann,S.H. (2003). Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis. Nat. Med. 9, 1039-1046.
Winau,F., Schwierzeck,V., Hurwitz,R., Remmel,N., Sieling,P.A., Modlin,R.L., Porcelli,S.A., Brinkmann,V., Sugita,M., Sandhoff,K., Kaufmann,S.H., and Schaible,U.E. (2004). Saposin C is required for lipid presentation by human CD1b. Nat. Immunol. 5, 169-174.
Winau,F., Weber,S., Sad,S., de Diego,J., Locatelli Hoops,S., Breiden,B., Sandhoff,K., Brinkmann,V., Kaufmann,S.H., and Schaible,U.E. (2006). Apoptotic vesicles cross-prime CD8 T cells and protect against tuberculosis. Immunity 24, 105-117.
Wunder,C.#, Winau,F.#, Churin,Y.#, Warnecke,D., Vieth,M., Lindner,B., Zähringer,U., Mollenkopf,H.J., Heinz,E., and Meyer,T.F. (2006). Cholesterol glucosylation promotes immune evasion by Helicobacter pylori. # First Authorship. Nat. Med. 12, 1030-1038.
Winau,F., Hegasy,G., Weiskirchen,R., Weber,S., Cassan,C., Sieling,P.A., Modlin,R.L., Liblau,R.S., Gressner,A.M., and Kaufmann,S.H. (2007). Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity 26, 117-129.
Darmoise,A., Teneberg,S., Bouzonville,L., Brady,R.O., Beck,M., Kaufmann,S.H., and Winau,F. (2010). Lysosomal alpha-galactosidase controls the generation of self lipid antigens for natural killer T cells. Immunity 33, 216-228.