(BOYSON): MOLECULAR DETERMINANTS OF NKT CELL ACTIVATION BY CD1D AND ITS LIGANDS

University Of Vermont & St Agric College, Burlington VT

Investigators

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ***Please note: Dr. Boyson "graduated" off the COBRE as of 10/1/2008. He now serves as a mentor for Dr. Jason Botten. Invariant natural killer T (iNKT) cells comprise a novel subset of T cells that has a profound effect on infectious disease, autoimmunity, tolerance induction, and tumor immunology. NKT cells can be activated through recognition of microorganism-derived glycolipids presented by CD1d (direct pathway), or through IL-12 and IL-18 produced by antigen presenting cells activated by TLR ligands (indirect pathway). Upon activation, NKT cells rapidly secrete large amounts of a wide variety of cytokines and activate other leukocyte subsets such as dendritic cells, macrophages, B cells, and natural killer cells. Given their relatively high frequency in the gut, liver, and lung, these observations suggest that NKT cells may play a role in early events of a developing immune response. During this funding period, we have focused our attention on investigation of genetic determinants of NKT cell function. We have published the observation that there is widespread variation in NKT cell number and function among different genetic backgrounds. These strain-dependent differences are correlated with significant physiological effects such as shared susceptibility to aGalCer-induced airway hyperreactivity (a cardinal feature of asthma), aGalCer-induced liver injury, and aGalCer-induced pregnancy loss. We have now extended this work by investigating the significance of strain-dependent variation in NKT cell number and function. We have found that strains exhibiting low NKT cell number and function, such as 129S1/SvImJ, respond poorly in vivo to LPS. We have also found that liver NKT cell number is under strictly controlled by the SLAM/CD2 locus on chromosome 1 which possesses numerous polymorphisms between strains. Most interesting, we have found using a congenic strain where the 129S1/SvImJ SLAM/CD2 locus was introgressed onto the C57BL/6J background that, in addition to controlling liver NKT cell number, the SLAM/CD2 locus controls the in vivo response to LPS. Taken together, our data suggest that SLAM-dependent control of NKT cell number modulates the in vivo response to TLR ligands. We are currently preparing a manuscript for submission. Publications 2008: Rymarchyk, S.L., H. Lowenstein, J. Mayette, S.R. Foster, D. Damby, I.W. Howe, I. Aktan, R.E. Meyer, M.E. Poynter, and J.E. Boyson. 2008. Widespread natural variation in NKT cell number and function. Immunology 125:331-343. Exley, M.A., R. Hou, A. Shaulov, E. Tonti, P. Dellabona, G. Casorati, O. Akbari, H.O. Akman, E.A. Greenfield, J.E. Gumperz, J.E. Boyson, S.P. Balk, and S.B. Wilson. 2008. Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR alpha-chain CDR3 loop. European Journal of Immunology 38(6):1756-1766. J.E. Boyson, I. Aktan, D. Barkhuff, and A. Chant. NKT cells at the maternal-fetal interface. 2008. Immunological Investigations 37:565-582. Olson Jr., C.M., T.C. Bates, H. Izadi, J.D. Radolf, S.A. Huber, J.E. Boyson, and J. Anguita. 2009. Local regulation of interferon gamma by invariant natural killer T cells modulates acute lyme carditis. Journal of Immunology 182(6): p. 3728-3734. Paveglio, S, J. Allard, S. Foster, J. Ather, M. Bevelander, J. Mayette, L. Whittaker, J.E. Boyson, and M.E. Poynter. Overexpression of IDO within mouse airway epithelial cells mitigates CD4+ T-cell activities during Aspergillus fumigatus antigen exposure (submitted). Mentoring Summaries: Elizabeth A. Bonney, M.D. As a member of the COBRE for the Vermont Center for Immunology and Infectious disease I have mentoring relationships with several levels of trainees within the COBRE, including graduate students and post doctoral fellows. I served as the mentor for Jon Boyson, who, as of June 2008 "graduated " to the level of Senior Faculty, and who currently mentors Jason Botten. Jon and I continue to collaborate on issues related to biology of abnormal pregnancy. I continue to offer support in terms of delineation and achievement of long-term career goals. We continue to meet approximately once every two months. Jason and I collaborate on using a mouse model better understand the immunobiology of infection with Lymphocytic choriomeningitis virus, particularly as it relates to tissue-specific immunity.