Insoo Kang, MD
Research & Publications
Biography
News
Research Summary
My lab is interested in understanding the immune system using human biological samples, clinical data, and animal models. In particular, we investigate T cells, monocytes and other innate immune cells, focusing on immunosenescence, autoimmunity, immunodeficiency, 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 and other immune cells.
Specialized Terms: Human T cell biology; Monocytes; Immunosenescence; Autoimmunity; Inflammation
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.
Coauthors
Research Interests
Aging; Inflammation; Rheumatology; T-Lymphocytes; Autoimmunity
Selected Publications
- Advances in Disease Mechanisms and Translational Technologies: Clinicopathologic Significance of Inflammasome Activation in Autoimmune Diseases.Kahlenberg JM, Kang I. Advances in Disease Mechanisms and Translational Technologies: Clinicopathologic Significance of Inflammasome Activation in Autoimmune Diseases. Arthritis & Rheumatology (Hoboken, N.J.) 2020, 72: 386-395. PMID: 31562704, PMCID: PMC7050400, DOI: 10.1002/art.41127.
- Immunological and Clinical Phenotyping in Primary Antibody Deficiencies: a Growing Disease Spectrum.Shin JJ, Liauw D, Siddiqui S, Lee J, Chung EJ, Steele R, Hsu FI, Price C, Kang I. Immunological and Clinical Phenotyping in Primary Antibody Deficiencies: a Growing Disease Spectrum. Journal Of Clinical Immunology 2020, 40: 592-601. PMID: 32239366, PMCID: PMC7260109, DOI: 10.1007/s10875-020-00773-y.
- IL-7 receptor alpha defines heterogeneity and signature of human effector memory CD8+ T cells in high dimensional analysis.Shin MS, Kim D, Yim K, Park HJ, You S, Dong X, Koumpouras F, Shaw AC, Fan R, Krishnaswamy S, Kang I. IL-7 receptor alpha defines heterogeneity and signature of human effector memory CD8+ T cells in high dimensional analysis. Cellular Immunology 2020, 355: 104155. PMID: 32619811, PMCID: PMC7415611, DOI: 10.1016/j.cellimm.2020.104155.
- Macrophage Migration Inhibitory Factor Regulates U1 Small Nuclear RNP Immune Complex-Mediated Activation of the NLRP3 Inflammasome.Shin MS, Kang Y, Wahl ER, Park HJ, Lazova R, Leng L, Mamula M, Krishnaswamy S, Bucala R, Kang I. Macrophage Migration Inhibitory Factor Regulates U1 Small Nuclear RNP Immune Complex-Mediated Activation of the NLRP3 Inflammasome. Arthritis & Rheumatology (Hoboken, N.J.) 2019, 71: 109-120. PMID: 30009530, PMCID: PMC6310104, DOI: 10.1002/art.40672.
- Transcriptomic analysis of human IL-7 receptor alpha low and high effector memory CD8+ T cells reveals an age-associated signature linked to influenza vaccine response in older adults.Park HJ, Shin MS, Kim M, Bilsborrow JB, Mohanty S, Montgomery RR, Shaw AC, You S, Kang I. Transcriptomic analysis of human IL-7 receptor alpha low and high effector memory CD8+ T cells reveals an age-associated signature linked to influenza vaccine response in older adults. Aging Cell 2019, 18: e12960. PMID: 31044512, PMCID: PMC6612637, DOI: 10.1111/acel.12960.
- DNA Methylation Regulates the Differential Expression of CX3CR1 on Human IL-7Rαlow and IL-7Rαhigh Effector Memory CD8+ T Cells with Distinct Migratory Capacities to the Fractalkine.Shin MS, You S, Kang Y, Lee N, Yoo SA, Park K, Kang KS, Kim SH, Mohanty S, Shaw AC, Montgomery RR, Hwang D, Kang I. DNA Methylation Regulates the Differential Expression of CX3CR1 on Human IL-7Rαlow and IL-7Rαhigh Effector Memory CD8+ T Cells with Distinct Migratory Capacities to the Fractalkine. Journal Of Immunology (Baltimore, Md. : 1950) 2015, 195: 2861-9. PMID: 26276874, PMCID: PMC4561204, DOI: 10.4049/jimmunol.1500877.
- IL-6 receptor α defines effector memory CD8+ T cells producing Th2 cytokines and expanding in asthma.Lee N, You S, Shin MS, Lee WW, Kang KS, Kim SH, Kim WU, Homer RJ, Kang MJ, Montgomery RR, Dela Cruz CS, Shaw AC, Lee PJ, Chupp GL, Hwang D, Kang I. IL-6 receptor α defines effector memory CD8+ T cells producing Th2 cytokines and expanding in asthma. American Journal Of Respiratory And Critical Care Medicine 2014, 190: 1383-94. PMID: 25390970, PMCID: PMC4299645, DOI: 10.1164/rccm.201403-0601OC.
- Human monocytes have increased IFN-γ-mediated IL-15 production with age alongside altered IFN-γ receptor signaling.Lee N, Shin MS, Kang KS, Yoo SA, Mohanty S, Montgomery RR, Shaw AC, Kang I. Human monocytes have increased IFN-γ-mediated IL-15 production with age alongside altered IFN-γ receptor signaling. Clinical Immunology (Orlando, Fla.) 2014, 152: 101-10. PMID: 24657713, PMCID: PMC4018768, DOI: 10.1016/j.clim.2014.03.003.
- Self double-stranded (ds)DNA induces IL-1β production from human monocytes by activating NLRP3 inflammasome in the presence of anti-dsDNA antibodies.Shin MS, Kang Y, Lee N, Wahl ER, Kim SH, Kang KS, Lazova R, Kang I. Self double-stranded (ds)DNA induces IL-1β production from human monocytes by activating NLRP3 inflammasome in the presence of anti-dsDNA antibodies. Journal Of Immunology (Baltimore, Md. : 1950) 2013, 190: 1407-15. PMID: 23315075, PMCID: PMC3563755, DOI: 10.4049/jimmunol.1201195.
- U1-small nuclear ribonucleoprotein activates the NLRP3 inflammasome in human monocytes.Shin MS, Kang Y, Lee N, Kim SH, Kang KS, Lazova R, Kang I. U1-small nuclear ribonucleoprotein activates the NLRP3 inflammasome in human monocytes. Journal Of Immunology (Baltimore, Md. : 1950) 2012, 188: 4769-75. PMID: 22490866, PMCID: PMC3347773, DOI: 10.4049/jimmunol.1103355.
- 1,25-Dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region.Kang SW, Kim SH, Lee N, Lee WW, Hwang KA, Shin MS, Lee SH, Kim WU, Kang I. 1,25-Dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region. Journal Of Immunology (Baltimore, Md. : 1950) 2012, 188: 5276-82. PMID: 22529297, PMCID: PMC3358577, DOI: 10.4049/jimmunol.1101211.
- Age-associated alteration in naive and memory Th17 cell response in humans.Lee JS, Lee WW, Kim SH, Kang Y, Lee N, Shin MS, Kang SW, Kang I. Age-associated alteration in naive and memory Th17 cell response in humans. Clinical Immunology (Orlando, Fla.) 2011, 140: 84-91. PMID: 21489886, PMCID: PMC3115516, DOI: 10.1016/j.clim.2011.03.018.
- Regulating human Th17 cells via differential expression of IL-1 receptor.Lee WW, Kang SW, Choi J, Lee SH, Shah K, Eynon EE, Flavell RA, Kang I. Regulating human Th17 cells via differential expression of IL-1 receptor. Blood 2010, 115: 530-40. PMID: 19965648, PMCID: PMC2810985, DOI: 10.1182/blood-2009-08-236521.
- Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus.Shah K, Lee WW, Lee SH, Kim SH, Kang SW, Craft J, Kang I. Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus. Arthritis Research & Therapy 2010, 12: R53. PMID: 20334681, PMCID: PMC2888202, DOI: 10.1186/ar2964.
- Dual roles of IL-15 in maintaining IL-7RalphalowCCR7- memory CD8+ T cells in humans via recovering the phosphatidylinositol 3-kinase/AKT pathway.Kim HR, Hwang KA, Kang I. Dual roles of IL-15 in maintaining IL-7RalphalowCCR7- memory CD8+ T cells in humans via recovering the phosphatidylinositol 3-kinase/AKT pathway. Journal Of Immunology (Baltimore, Md. : 1950) 2007, 179: 6734-40. PMID: 17982063, DOI: 10.4049/jimmunol.179.10.6734.
- Down-regulation of IL-7Ralpha expression in human T cells via DNA methylation.Kim HR, Hwang KA, Kim KC, Kang I. Down-regulation of IL-7Ralpha expression in human T cells via DNA methylation. Journal Of Immunology (Baltimore, Md. : 1950) 2007, 178: 5473-9. PMID: 17442928, DOI: 10.4049/jimmunol.178.9.5473.
- Altered IL-7Ralpha expression with aging and the potential implications of IL-7 therapy on CD8+ T-cell immune responses.Kim HR, Hong MS, Dan JM, Kang I. Altered IL-7Ralpha expression with aging and the potential implications of IL-7 therapy on CD8+ T-cell immune responses. Blood 2006, 107: 2855-62. PMID: 16357322, PMCID: PMC1440715, DOI: 10.1182/blood-2005-09-3560.
- Defective control of latent Epstein-Barr virus infection in systemic lupus erythematosus.Kang I, Quan T, Nolasco H, Park SH, Hong MS, Crouch J, Pamer EG, Howe JG, Craft J. Defective control of latent Epstein-Barr virus infection in systemic lupus erythematosus. Journal Of Immunology (Baltimore, Md. : 1950) 2004, 172: 1287-94. PMID: 14707107, DOI: 10.4049/jimmunol.172.2.1287.
- Age-associated change in the frequency of memory CD4+ T cells impairs long term CD4+ T cell responses to influenza vaccine.Kang I, Hong MS, Nolasco H, Park SH, Dan JM, Choi JY, Craft J. Age-associated change in the frequency of memory CD4+ T cells impairs long term CD4+ T cell responses to influenza vaccine. Journal Of Immunology (Baltimore, Md. : 1950) 2004, 173: 673-81. PMID: 15210831, DOI: 10.4049/jimmunol.173.1.673.
Clinical Trials
Conditions | Study Title |
---|---|
Immune System | Yale Lupus and Connective Tissue Disease Bio-Repository / Yale Rheumatology Bio-Repository |
Arthritis | Yale Rheumatology Program Patient Registry and Bio-Repository |
Diseases of the Respiratory Systems; COVID-19 Inpatient; COVID-19 Outpatient | A Study Tracking Health Care Workers Exposed to COVID-19 |