Insoo Kang, MD

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.