We study innate immune cell responses to infectious disease and malignancy, with a particular focus on natural killer (NK) cells, the third major population of lymphocytes. Our current research is aimed at understanding how NK cells mount effective immune responses against viral infections (e.g., herpesviruses, retroviruses and influenza virus).
We have recently discovered a novel subset of human NK cells that displays very potent anti-viral responsiveness. This subset is characterized by deficient expression of the signaling adaptor FcRγ, which normally associates with the IgG Fc receptor (CD16) as a homo-dimer or a hetero-dimer with CD3ζ, a second CD16-associated adaptor, as observed in conventional NK cells (cartoon below). However, FcRγ-deficient NK cells, termed ‘g-NK cells’, express CD3ζ at normal levels. Importantly, we have found that g-NK cells exhibit greatly enhanced functional and proliferative responses toward target cells infected with a variety of viruses in the presence of virus-specific antibodies (Ab).
We have detected g-NK cells in approximately 40% of the healthy donors tested, and the presence of these cells is associated with prior infection by cytomegalovirus (CMV), a common herpesvirus that infects billions of people worldwide.
Our research aims to understand 1) how g-NK cells function better than conventional NK cells, 2) how g-NK cells are generated and maintained, and 3) what role g-NK cells play in immune responses to viral infections.
We are also pursuing a better understanding of NK cell functional and proliferative responses during hematopoiesis following bone marrow transplantion in humans, and during viral infection in rhesus macaques. In particular, we are working to identify molecular and biochemical mechanisms by which NK cells are activated in response to infection with CMV or SIV. We are also investigating the role that g-NK cells play in anti-tumor responses.
Epigenetic modification and antibody-dependent expansion of memory-like NK cells in human cytomegalovirus-infected individuals (2015) Lee J, Zhang T, Hwang I, Kim A, Nitschke L, Kim M, Scott JM, Kamimura Y, Lanier LL, Kim S. Immunity. 42(3):431-442.
Beli E, Duriancik DM, Clinthorne JF, Lee T, Kim S, Gardner EM. (2014) Natural killer cell development and maturation in aged mice. Mech Ageing Dev. 135:33-40.
Zhang T, Scott JM, Hwang I, Kim S. (2013) Antibody-dependent memory-like NK cells distinguished by FcRg-deficiency. J Immunol: Cutting Edge. 190(4):1402-1406.
Hwang I, Zhang T, Scott JM, Kim AR, Lee T, Kakarla T, Kim A, Sunwoo JB, Kim S. (2012) Identification of human NK cells that are deficient for signaling adaptor FcRg and specialized for antibody-dependent immune functions. Int Immunol. 24:793-802.
Hwang, I, Scott, JM, Kakarla, T, Duriancik, DM, Choi, S, Cho, C, Lee, T, Park, H, French, AR, Beli, E, Gardner, E, Kim S. (2012) Activation mechanisms of natural killer cells during influenza virus infection. PLoS One. 2012;7(12):e51858.
Beli E, Clinthorne JF, Duriancik DM, Hwang I, Kim S, Gardner EM. (2011) Natural killer cell function is altered during the primary response of aged mice to influenza infection. Mech Ageing Dev. 2011 Oct;132(10):503-510.
Jonsson AH, Yang L, Kim S, Taffner SM, Yokoyama WM. (2010) Effects of MHC class I alleles on licensing of Ly49A+ NK cells. J Immunol. 184(7):3424-3432.
Kim S, Sunwoo JB, Yang L, Choi T, Song YJ, French AR, Vlahiotis A, Piccirillo JF, Cella M, Colonna M, Mohanakumar T, Hsu KC, Dupont B, Yokoyama WM. (2008) HLA alleles determine differences in human natural killer cell responsiveness and potency. Proc Natl Acad Sci U S A. 105(8):3053-3058.
Kim S, Poursine-Laurent J, Truscott SM, Lybarger L, Song YJ, Yang L, French AR, Sunwoo JB, Lemieux S, Hansen TH, Yokoyama WM. (2005) Licensing of natural killer cells by host MHC class I. Nature. 436:709-713
Kim S, Iizuka K, Kang HS, Dokun A, French AR, Greco S, Yokoyama WM. (2002) In vivo developmental stages in murine natural killer cell maturation. Nature Immunol. 3(6):523-528.
Dokun AO*, Kim S*, Smith HR, Kang HS, Chu DT, Yokoyama WM. (2001) Specific and nonspecific NK cell activation during virus infection. Nature Immunol. 2(10):951-956.
Kim S, Iizuka K, Aguila HL, Weissman IL, Yokoyama WM. (2000) In vivo natural killer cell activities revealed by natural killer cell-deficient mice. Proc Natl Acad Sci U S A. 97(6):2731-2736.