Aging; Rheumatology; T-Lymphocytes; Autoimmunity
Skin Diseases Research Center, Yale
My laboratory investigates human T cell biology, focusing on immunosenescence and autoimmunity. Aging is associated with diminished immune responses against pathogens and malignancy. However, the underlying mechanisms for these findings are largely unknown. Recently, we investigated the effect of aging on the IL-7-mediated CD8 + T cell survival since IL-7 is critical for the generation and survival of memory CD8 + T cells. Cells expressing IL-7 receptor (R) alpha (a) high and low were identified in CD45RA+ effector memory (EM CD45RA+, CD45RA+ CCR 7+) CD8+ T cell subset. The elderly (age = 65) had an increased frequency of EM CD45RA+ IL-7Ra low CD8+ T cells leading to decreased signaling and survival responses to IL-7 compared to the young (age = 40). These EM CD45RA+ IL-7Ralow cells were largely antigen-experienced (CD27- CD28-), replicatively senescent (CD57+) and perforin high CD8+ T cells that had decreased IL-7Ra mRNA expression. These findings indicate that aging affects IL-7Ra expression by EM CD45RA+ CD8+ T cells, leading to impaired signaling and survival responses to IL-7.
Specialized Terms: Human T cell biology; Immunosenescence; Autoimmunity
Extensive Research Description
Currently, we are investigating the mechanisms for how IL-7Ralow memory CD8+ T cells maintain low levels of IL-7Ra mRNA expression focusing on epigenetic regulation of genes. In addition, we are studying how IL-7Ralow memory CD8+ T cells are maintained despite impaired survival and proliferation in response to IL-7 and T cell receptor (TCR) triggering, respectively. We are also analyzing the effect of aging on regulatory T cells in humans. Lastly, our lab investigates alterations in T cell phenotype and function in patients with lupus in collaboration with Dr. Joe Craft. Recently, we reported that patients with lupus have defective control of latent Epstein- Barr virus (EBV) infection as evidence by increased EBV viral loads that stem from altered T cell immune responses to EBV. Our research will advance our understanding in the areas of immunosenescence and autoimmunity.
- 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
- 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
- M Shin, Y Kang, N Lee, S Kim, K 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)