Baruj Benacerraf Professor of Microbiology & Immunobiology
Chairman, Department of Cancer Immunology & AIDS
1 Jimmy Fund Way
Smith Bldg., 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. 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 (1). While analysis of the immune system has defined a sublineage of CD4+ regulatory T cells that can inhibit excessive inflammatory immune responses, more recent studies have defined a lineage of regulatory CD8 T cells that are genetically programmed to inhibit development of autoantibody formation and SLE-like disease (2). These CD8+ Treg, which are programmed to inhibit the activation and expansion of follicular helper T cells (TFH), express a triad of surface receptors – CD44, CD122 and the inhibitory Ly49 receptor –and a T cell receptor (TCR) that recognizes Qa-1–peptide complexes expressed by TFH cells (3). These studies have fundamental relevance to understanding the immune system and suggest new approaches to the treatment of SLE and other autoimmune disorders.
More recent studies have extended the functional reach of the natural killer (NK) cell system to include regulation of adaptive T cell responses, suggesting new clinical strategies for elimination of autoreactive T cells that drive autoimmune disorders, including SLE (4), a murine model of MS, EAE (5), as well as a murine model of rheumatoid arthritis, termed collagen-induced arthritis (Leavenworth et al, 2011, in prep).
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; 2008). Elaboration of the cytokines Osteopontin and IFNα 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.
Lu L, Kim HJ, Werneck MB, 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.
Kim HJ, Verbinnen B, Tang X, Lu L, Cantor H. (2010) Inhibition of follicular T helper cells by CD8+ Treg is essential for self tolerance. Nature 467:328-332.
Kim HJ et al. (2011) CD8+ T regulatory cells express the Ly49 class I MHC receptor and are defective in autoimmune-prone B6-Yaa mice. Proc Natl Acad Sci U S A 108:2010-2015.
Lu L et al. (2007) Regulation of activated CD4+ T cells by NK cells via the Qa-1-NKG2A pathway. Immunity 26:593-604.
Leavenworth JW et al. (2010) Analysis of the cellular mechanism underlying inhibition of EAE after treatment with anti-NKG2A F(ab')2. Proc Natl Acad Sci U S A 107:2562-2567.
Last Update: 1/6/2014