Aging; Rheumatology; T-Lymphocytes; Autoimmunity
Skin Diseases Research Center, Yale
My lab is interested in understanding the human immune system using biological samples and clinical data. In particular, we investigate human T cells and monocytes, focusing on immunesenescence, autoimmunity and inflammation. We have defined subsets of human T cells with distinct cellular characteristics based on the expression of cytokine receptors and their changes in aging and inflammatory diseases as well as the interactions of such cell subsets with monocytes.
Specialized Terms: Human T cell biology; monocytes; Immunosenescence; Autoimmunity
Extensive Research Description
Studying the role of cytokine receptors and cytokines in defining human T cell subsets and regulating their functions in health and disease (aging and inflammation).
The cytokine IL-7 is essential for the homeostasis of memory T cells. We identified two novel subsets of effector memory (EM) CD8+ T cells with high and low levels of IL-7 receptor α chain expression (IL-7Rαhigh and low) in human peripheral blood. Compared to IL-7Rαhigh cells, IL-7Rαlow EM CD8+ T cells were highly antigen-experienced, cytotoxic and replication senescent cells.My lab found the expansion of IL-7Rαlow EM CD8+ T cells in older adults as well as in patients with SLE, which can be related to repetitive immune stimulations. Alternatively, but not mutually exclusive, the expansion of IL-7Rαlow EM CD8+ T cells could be driven by the cytokine IL-15 which is essentially involved in CD8+ T cell homeostasis.Also, we have found that DNA methylation, a mechanism involved in regulating gene expression, was responsible in part for conferring unique pro-inflammatory traits of IL-7Rαhigh and low EM CD8+ T cells.
While studying IL-7Rαhigh and low EM CD8+ T cells in human peripheral blood, my lab found a unique subset of EM CD8+ T cells that express high levels of IL-6Ra in addition to IL-7Rα.These cells that potently proliferated, survived, and produced high levels of the Th2-type cytokines IL-5 and IL-13 had increased levels of the transcription factor GATA3 in comparison to other EM CD8+ T cells.In fact, GATA3 was required for IL-6Rα expression. Patients with asthma, a Th2 response-related disease, had an increased frequency of IL-6Rαhigh EM CD8+ T cells in peripheral blood compared to healthy controls.Our study first identified human IL-6Rαhigh EM CD8+ T cells that may serve as a reservoir for effector CD8+ T cells, particularly the ones producing Th2-type cytokines.
Defining the role of IL-1β, its receptor and NLRP3 inflammasome in promoting Th17 cell response and inflammation in health and disease.
While conducting studies on CD8+ T cell in humans, my lab has investigated human CD4+ T cells in health and disease (e.g. SLE).This is particularly important given the dynamic interactions among different immune cells.T helper (Th) 17 cells are a recently identified subset of Th cells that produce the pro-inflammatory cytokine IL-17.In fact, we reported an increased frequency of Th17 cells that correlated with disease activity in patients with SLE.Cytokines such as IL-1β is essential for the development of Th17 cells.My lab identified a subset of CD4+ T cells with the expression of IL-1 receptor 1 (IL-1R1) that potently produced IL-17 in human naïve and memory CD4+ T cells.This work, which first showed a potential role for IL-1R1 as a molecule identifying Th17 cells in humans, was published in Blood and cited as a “Must Read” paper by Faculty of 1000 Biology.To find the possible mechanism for increased IL-17 production in lupus patients, we initiated a study on whether lupus target autoantigen and antibody immune complexes could activate human monocytes, a primary source of IL-1β, leading to the production of IL-1β which increases Th17 cell response.In fact, my lab has found that lupus autoimmune complexes of U1-snRNP and dsDNA could induce IL-1β from healthy human monocytes via activating the NLRP3 inflammasome, a multi-protein complex that cleaves pro-IL-1β into the active IL-1β.These studies first show the possible role of the caspase-1-containing NLRP3 inflammasome in the pathogenesis of lupus, providing a scientific rationale for targeting this molecular complex as tested in animal models of lupus.
- MS Shin, SY You, Y Kang, NE Lee, SA Yoo, K Park, KS Kang, SH Kim, S Mohanty, AC Shaw, RR Montgomery, DH Hwang, I Kang. 2015. DNA methylation regulates the differential expression of CX3CR1 on human IL-7R alpha low and high effector memory CD8+ T cells with distinct migratory capacities to the fractalkine. J Immunol. 195:2681-2689. PMCID: PMC4561204.
- NE Lee, SY You, MS Shin, WW Lee, KS Kang, SH.Kim, WU Kim, RJ Homer, MJ Kang, RR Montgomery, CS Dela Cruz, AC Shaw, PJ Lee, GL Chupp, DH Hwang, I Kang. 2014. L-6 receptor a defines effector memory CD8+ T cells producing Th2 cytokines and expanding in asthma. Am J Respir Crit Care Med. 190:1383-94
- NE Lee, MS Shin MS, KS Kang, SA Yoo, S Mohanty, RR Montgomery, AC Shaw, I Kang. Human monocytes have increased IFN-γ-mediated IL-15 production with age alongside altered IFN-γ receptor signaling. Clinical Immunol. 2014, 152:101-110. PMCID: PMC4018768
- MS Shin, Y Kang, NE Lee, ER Wahl, SH Kim, KS Kang, R Lazova and I Kang. 2013. Self dsDNA induces IL-1ß production from human monocytes by activating NLRP3 inflammasome in the presence of anti-dsDNA antibodies. J Immunol 190:1407-1415. PMCID: PMC3563755
- SW Kang, SH Kim, NE Lee, WW Lee, KA Hwang, MS Shin, SH Lee, WU Kim and I Kang. 2012. 1,25(OH)2 vitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved non-coding sequence region. J Immunol 188:5276-5282. PMCID: PMC3358577
- MS Shin, Y Kang, NE Lee, SH Kim, KS Kang, R Lazova and I Kang. 2012. U1-snRNP activates the NLRP3 inflammasome in human monocytes. J. Immunol 188:4769-75. PMCID: PMC3347773
- JS Lee, WW Lee, SH Kim, NE Lee, MS Shin, SW Kang and I Kang. 2011. Age-associated alteration in naïve and memory Th17 cell response in humans. Clinical Immunol 140:84-91. PMCID: PMC3115516
- WW Lee, SW Kang, J Choi, SH Lee, K Shah, EE Eynon, RA Flavell and I Kang. 2010. Regulating Human Th17 Cells Via Differential Expression of IL-1 Receptor. Blood. 115:530-540 (cited as a Must Read paper in Faculty of 1000 Biology). PMCID: PMC2810985
- K Shah, WW Lee, SW Kang, SH Kim, SH Lee, J Craft and I Kang. 2010. Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus. Arthritis Res Ther. 12:R53. PMCID: PMC2888202
- HR Kim*, KA Hwang * and I Kang. 2007. Dual roles of IL-15 in maintaining IL-7R alpha low CCR7- memory CD8+ T cells in humans via recovering the PI3K/AKT pathway. J Immunol. 179:6734-6740 (cited in “IN THIS ISSUE” in the same issue). *Equally contributed
- HR Kim, KA Hwang and I Kang. 2007. The role of DNA methylation in differentially regulating IL-7Ra expression in human T cells. J Immunol. 178:5473-5479
- HR Kim, MS Hong, JM Dan and I Kang. 2006. Altered IL-7Ra expression with aging and the potential implications of IL-7 therapy on CD8+ T cell immune responses. Blood. 107:2855-2862 (accompanied by commentary entitled “IL-7 comes of age” published in the
- I Kang, T. Quan, H. Nolasco, SH Park, MS Hong, GJ Howe and J Craft. 2004. Defective control of latent EBV infection in patients with systemic lupus erythematosus. J Immunol 172:1287-1294.
- I Kang *, MS Hong, H Nolasco, SH Park, JM Dan, JY Choi and J Craft. 2004. Age-associated change in the frequency of memory CD4+ T cells impairs long-term CD4+ T cell responses to influenza vaccine. J Immunol 173:673-681. (*Corresponding Author)