Showing papers by "Dong-Ming Su published in 2020"
TL;DR: How T cell adaptive immunity mediates inflammaging and plays a crucial role in the progression of age-related neurological and cardiovascular diseases, as well as cancer is described.
Abstract: Immune system aging is characterized by the paradox of immunosenescence (insufficiency) and inflammaging (over-reaction), which incorporate two sides of the same coin, resulting in immune disorder. Immunosenescence refers to disruption in the structural architecture of immune organs and dysfunction in immune responses, resulting from both aged innate and adaptive immunity. Inflammaging, described as a chronic, sterile, systemic inflammatory condition associated with advanced age, is mainly attributed to somatic cellular senescence-associated secretory phenotype (SASP) and age-related autoimmune predisposition. However, the inability to reduce senescent somatic cells (SSCs), because of immunosenescence, exacerbates inflammaging. Age-related adaptive immune system deviations, particularly altered T cell function, are derived from age-related thymic atrophy or involution, a hallmark of thymic aging. Recently, there have been major developments in understanding how age-related thymic involution contributes to inflammaging and immunosenescence at the cellular and molecular levels, including genetic and epigenetic regulation, as well as developments of many potential rejuvenation strategies. Herein, we discuss the research progress uncovering how age-related thymic involution contributes to immunosenescence and inflammaging, as well as their intersection. We also describe how T cell adaptive immunity mediates inflammaging and plays a crucial role in the progression of age-related neurological and cardiovascular diseases, as well as cancer. We then briefly outline the underlying cellular and molecular mechanisms of age-related thymic involution, and finally summarize potential rejuvenation strategies to restore aged thymic function.
180 citations
TL;DR: Thymic involution may be potentially beneficial to antitumor immunity, since the involuted thymus increases output of self-reactive T cells, which may recognize certain tumor-associated self-antigens and enhance antitumors immunity.
Abstract: The thymus is the central lymphoid organ for T cell development, a cradle of T cells, and for central tolerance establishment, an educator of T cells, maintaining homeostatic cellular immunity. T cell immunity is critical to control cancer occurrence, relapse, and antitumor immunity. Evidence on how aberrant thymic function influences cancer remains largely insufficient, however, there has been recent progress. For example, the involuted thymus results in reduced output of naive T cells and a restricted T cell receptor (TCR) repertoire, inducing immunosenescence and potentially dampening immune surveillance of neoplasia. In addition, the involuted thymus relatively enhances regulatory T (Treg) cell generation. This coupled with age-related accumulation of Treg cells in the periphery, potentially provides a supportive microenvironment for tumors to escape T cell-mediated antitumor responses. Furthermore, acute thymic involution from chemotherapy can create a tumor reservoir, resulting from an inflammatory microenvironment in the thymus, which is suitable for disseminated tumor cells to hide, survive chemotherapy, and become dormant. This may eventually result in cancer metastatic relapse. On the other hand, if thymic involution is wisely taken advantage of, it may be potentially beneficial to antitumor immunity, since the involuted thymus increases output of self-reactive T cells, which may recognize certain tumor-associated self-antigens and enhance antitumor immunity, as demonstrated through depletion of autoimmune regulator (AIRE) gene in the thymus. Herein, we briefly review recent research progression regarding how altered thymic function modifies T cell immunity against tumors.
30 citations
TL;DR: In this paper, a thymic rejuvenation strategy was proposed by combining two types of promoter-driven (Rosa26CreERT and FoxN1Cre) Cre-mediated FOXN1-reprogrammed embryonic fibroblasts (Fthis papers).
Abstract: Age-associated systemic, chronic inflammation is partially attributed to increased self-autoreactivity, resulting from disruption of central tolerance in the aged, involuted thymus. This involution causally results from gradually decreased expression of the transcription factor FOXN1 in thymic epithelial cells (TECs), whereas exogenous FOXN1 in TECs can partially rescue age-related thymic involution. TECs induced from FOXN1-overexpressing embryonic fibroblasts can generate an ectopic de novo thymus under the kidney capsule, and intrathymic injection of naturally young TECs can lead to middle-aged thymus regrowth. Therefore, as a thymic rejuvenation strategy, we extended these 2 findings by combining them with 2 types of promoter-driven (Rosa26CreERT and FoxN1Cre) Cre-mediated FOXN1-reprogrammed embryonic fibroblasts (FREFs). We engrafted these FREFs directly into the aged murine thymus. We found substantial regrowth of the native aged thymus with rejuvenated architecture and function in both males and females, exhibiting increased thymopoiesis and reinforced thymocyte negative selection, along with reduced senescent T cells and autoreactive T cell-mediated inflammation in old mice. Therefore, this approach has preclinical significance and presents a strategy to potentially rescue decreased thymopoiesis and perturbed negative selection to substantially, albeit partially, restore defective central tolerance and reduce subclinical autoimmune symptoms in elderly people.
16 citations
TL;DR: This poster presents a probabilistic procedure called a “cell reprograming assay” (CAS) to characterize the immune response of the immune system to treat central giant cell granuloma.
Abstract: Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, TX, United States, Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX, United States, Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX, United States, Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States, Department of Anatomy and Developmental Biology, Monash University, Melbourne, VIC, Australia, 6 Fred Hutchinson Cancer Research Center and the University of
2 citations
TL;DR: A novel rejuvenation strategy via the FOXN 1-TEC axis using induced two types of FOXN1-overexpressing embryonic fibroblasts by intrathymic injection is able to counteract age-related thymic involution, which rescued negative selection, thereby, reducing peripheral T cell-associated inflammaging conditions.
Abstract: Age-associated systemic, chronic, sterile inflammatory condition (inflammaging) is partially attributed to increased self (auto)-reactivity, resulting from disruption of central tolerance in the aged, involuted thymus. Age-related thymic involution causally results from gradually declined expression of the transcription factor forkhead box N1 (FOXN1) in thymic epithelial cells (TECs), while exogenous FOXN1 in TECs can significantly rescue age-related thymic involution. Given the findings that induced TECs (iTECs) from FOXN1-overexpressing embryonic fibroblasts can generate an ectopic de novo thymus under the kidney capsule and intra-thymically injected natural young TECs can lead to middle-aged thymus regrowth, we sought to expand upon these two findings by applying them as a novel thymic rejuvenation strategy with two types of promoter-driven (Rosa26CreERT and FoxN1Cre) Cre-mediated iTECs. We engrafted iTECs, rather than natural young TECs, directly into the aged thymus and/or peri-thymus and found a significantly rejuvenated architecture and function in the native aged murine thymus. The engrafted iTECs drove regrowth of the aged thymus in both male and female mice, showing not only increased thymopoiesis, but also reinforcement of thymocyte negative selection, thereby, reducing senescent T cells and auto-reactive T cell-mediated inflammaging phenotypes in old mice. Therefore, this is a promising thymic rejuvenation strategy with preclinical significance, which can potentially rescue declined thymopoiesis and impaired negative selection to significantly, albeit partially, restore the defective central tolerance and reduce subclinical chronic inflammatory symptoms in the elderly. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=165 HEIGHT=200 SRC="FIGDIR/small/995357v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@7f8cfborg.highwire.dtl.DTLVardef@d1c4org.highwire.dtl.DTLVardef@1cbc905org.highwire.dtl.DTLVardef@1fa9e8d_HPS_FORMAT_FIGEXP M_FIG C_FIG A novel rejuvenation strategy via the FOXN1-TEC axis using induced two types of FOXN1-overexpressing embryonic fibroblasts (termed iTECs) by intrathymic injection is able to counteract age-related thymic involution, which rescued negative selection, thereby, reducing peripheral T cell-associated inflammaging conditions.