Brigham and Women's Hospital
75 Francis Street
Thorn Building 1405
Boston, MA 02115
With backgrounds in immunology/virology, we study CD1d-restricted ‘NKT’ cells, CD1d+ dendritic (DC) and other cells with which they interact, and how to utilize this knowledge in the clinic. A major heterogeneous population of T cells express certain NK markers: ‘natural killer T cells’ (NKT). Within this population are most CD1d-restricted T cells, including both polyclonal and ‘invariant’ NKT (iNKT). iNKT are CD4+ or CD4-CD8- with important roles in regulating immunity, including antiviral and antitumor responses. iNKT express restricted T cell receptor repertoire (human Vα24-Jα18 preferentially with Vβ11). Polyclonal and iNKT recognize non-polymorphic MHC class I-like CD1d, in conjunction with glycolipids that remain to be definitively identified. iNKT specifically respond to semiphysiological CD1d-presented α-galactosylceramide (αGalCer), isolated from sponges for antitumor activity. We examine various NKT from human blood, liver, and bone marrow as well as in vivo and in vitro for mice. Our work involves phenotypic and functional studies. This includes defining related anti-tumor and anti-viral roles of NKT. Th1-biasing subsets of NKT can promote DC maturation and cellular immunity (NK cells and lymphocytes). We found that poly-virus susceptible immuno-deficient patients as well as cancer patients with a wide range of malignancies have fewer and defective iNKT with compromised Th1 activity. These altered iNKT may suppress natural anti-tumor and anti-viral activities, but we have found the defect is reversible in vitro. We are investigating the potential of these cells as direct therapy by ‘translating’ our work to patients by supporting a Harvard Cancer Center phase 1 iNKT cell clinical trial using a monoclonal antibody we developed specific for iNKT. We have multiple further collaborations and are following up our identification of a physiological role for NKT in resistance to acute virus infections through their activation of NK and lymphocytes.
iNKT are also required for induction of tolerance/anergy in some models and loss of iNKT is associated with development of autoimmune diseases, including diabetes in humans and NOD mice.
Immunoregulatory/immunosuppressive functions of iNKT are apparently mediated by Th2 cytokines including IL-4, -10, and -13, but how iNKT decide on Th1, Th2 or Treg-type responses remains unclear. Significantly, ‘non-invariant’ NKT can suppress antitumor responses. Conversely, murine liver-derived CD4- iNKT most potently inhibit tumor growth.
iNKT:DC interactions have profound effects on immune regulation. Unlike CD1a-c, DC constitutively express CD1d, and αGalCer-loaded DC mediate activation of iNKT in vitro and in vivo, including cancer patient iNKT, with consequent DC maturation. iNKT activation and IFNγ production are markedly enhanced by induced DC IL-12. Activated iNKT CD40L can in turn activate DC through CD40, with iNKT IFNγ further stimulating DC IL-12. By these interactions, iNKT amplify IL-12 production by DC, consistent with requirement for iNKT in responses to physiological IL-12. Significantly, we found ligation of CD1d on human monocytes/DC can activate NFκB, leading to IL-12 production and DC maturation, providing another mechanism for iNKT regulation of DC function. Interestingly, the profile of chemokine receptors of blood iNKT indicates primarily trafficking to peripheral tissues, consistent with biological function being to stimulate immature tissue DC maturation. Interestingly, we observed patients with circulating IFNγ-producing-NKT correlate with better prognosis in hematological malignancies. Overall, studies in mice and early clinical trials support our efforts to enhance NKT function in cancer. Similarities between NKT protection in viral and tumor immunity in both models and humans ex vivo/in vitro strongly argue for clinical exploitation of this powerful immune amplification system for viral infections too.
Yue, S.C., R. Wang, A. Shaulov, S.P. Balk, & M.A. Exley. (2009) Direct CD1d-mediated stimulation of APC IL-12 production & protective immune response to virus infection in vivo. J. Immunol. 184:268-76. e-Pub. Nov. 30. PMID: 19949077. PMC Journal – In Process. http://www.jimmunol.org/cgi/reprint/184/1/268
Nowak M, Arredouani MS, Tun-Kyi A, Sanda MG, Balk SP, Exley, MA. Defective activation of invariant natural killer T cells by CD1d+ murine TRAMP prostate tumor cells is corrected by interleukin-12 and alpha-galactosylceramide. PLoS One. June 25: 5(6): e11311. PMCID: PMC2892484. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0011311
Lynch L, Nowak M, Varhese B, Clark J, Hogan A, Toxavidis V, Balk S, O’Shea D, O’Farrelly C, Exley MA. Unique Adipose Tissue Invariant Natural Killer T Cells Protect Against Diet-Induced Obesity and Metabolic Disorder Through Regulatory Cytokine Production. Immunity. Sep 12. pii: S1074-7613(12)00379-2. doi: 10.1016/j.immuni.2012.06.016. [Epub ahead of print]
Li S, Vriend LEM, Nasser IM, Popov Y, Afdhal NH, Koziel MJ, Schuppan D, Exley MA, Alatrakchi N. 2012. Hepatitis C virus-specific T cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis. Hepatology. Jul 14. doi: 10.1002/hep.25951. [Epub ahead of print]
Exley, MA., R. Hou, A. Shaulov, E. Tonti, P. Dellabona, G. Casorati, O. Akbari, H.O. Akman, E. Greenfield, J. Gumperz, J. Boyson, S. Balk, & B. Wilson (2008) Selective activation, expansion, and monitoring of human iNKT cells with a mAb specific for TCR -chain CDR3 loop. Eur. J. immunol. 20:1756-6. PMCID: PMC2864538.
Last Update: 9/5/2013