Baruj Benacerraf Professor of Pathology
Chairman, Department of Cancer Immunology & AIDS
Dana-Farber Cancer Institute
1 Jimmy Fund Way, Smith Building, Room 722
Boston, MA 02115
The focus of the lab is on the contribution of T cell subsets to the maintenance of protective immunity and prevention of autoimmune disease. Our studies of T cell development in the thymus have defined a new kinase (MINK) that is activated after engagement of the TCR and self peptides that initiates a pathway culminating in cellular apoptosis (negative selection).
A comprehensive understanding of complex biological information systems, including the immune system and nervous system, requires definition of cells that are genetically programmed to suppress signal transmission and inhibit cellular responses (Lu et al., 2008). Analysis of the immune system has defined a sublineage of CD4+ T cells, termed CD4+ Treg, that can inhibit excessive inflammatory immune responses. However, regulatory T cells that are genetically programmed to inhibit development of autoantibody formation and SLE-like disease had not been defined until recently.
After stimulation by class I MHC–peptide complexes, the majority of CD8+ T cells differentiate into memory and effector cells that secrete cytokines and lyse target cells recognized as foreign. We have defined a subset of CD8+ T cells (CD8+ Treg) that prevents autoantibody formation and maintains self tolerance, an essential feature of the adaptive immune system (Kim et al., 2010). Identification of a suppressive sublineage of CD8 T cells essential to prevent the generation of pathogenic autoantibody production and to ensure self tolerance has fundamental relevance to understanding the immune system and suggests new approaches to the treatment of SLE and other autoimmune disorders.
More recent studies have extended the functional reach of the NK system to include regulation of adaptive T cell responses and suggest a new clinical strategy for elimination of autoreactive T cells that drive autoimmune disorders, including SLE (Lu et al., 2007).
Finally, studies of the differentiation of T-helper cells have defined an interaction between dendritic cells and T cells that regulates the development of Th1 cells and Th17 cells (Shinohara et al., 2006; Shinohara et al., 2008). Elaboration of the cytokines Osteopontin and IFNa promotes the Th1 response and suppresses the Th17 response, establishing the pattern of T-helper cell differentiation displayed during the large majority of immune responses.
Kim, H.-J., Verbinnen, B., Tang, X., Lu, L., and Cantor, H. (2010). Inhibition of follicular T helper cells by CD8+ Treg is essential for self tolerance. Nature , in press.
Lu, L., Ikizawa, K., Hu, D., Werneck, M.B.F., Wucherpfennig, K.W., and Cantor, H. (2007). Regulation of activated CD4+ T cells by NK cells via the Qa-1-NKG2A pathway. Immunity 26, 593-604.
Lu, L., Kim, H.J., Werneck, M.B., and Cantor, H. (2008). Regulation of CD8+ regulatory T cells: Interruption of the NKG2A-Qa-1 interaction allows robust suppressive activity and resolution of autoimmune disease. Proc. Natl. Acad. Sci. U. S. A 105, 19420-19425.
Shinohara, M.L., Kim, J.-H., Garcia, V.A., and Cantor, H. (2008). Engagement of the Type-I interferon receptor on dendritic cells inhibits promotion of Th17 cells: Role of intracellular Osteopontin. Immunity 29, 68-78.
Shinohara, M.L., Lu, L., Bu, J., Werneck, M.B.F., Kobayashi, K., Glimcher, L.H., and Cantor, H. (2006). Osteopontin expression is essential for IFN-a production by plasmacytoid dendritic cells. Nat. Immunol. 7, 498-506.
Immunology webpage updated 7/27/2010