An NKT-mediated autologous vaccine generates CD4 T-cell-dependent potent antilymphoma immunity

Chung, Yeonseok,Qin, Hong,Kang, Chang-Yuil,Kim, Sanghee,Kwak, Larry W.,Dong, Chen American Society of Hematology 2007 Blood Vol.110 No.6

<B>Abstract</B><P>Relapses occurring in most patients with lymphoma after antibody or chemotherapy highlight a need for effective vaccination approaches. Autologous tumors are ideal sources of patient-specific tumor antigens for vaccines; however, their poor immunogenicity has been a major obstacle in practice. Natural killer T (NKT) cells have recently emerged as crucial regulators of autoimmunity and tumor immunosurveillance. Here, we show that an autologous lymphoma vaccine that activates NKT cells generated tumor-specific protective immunity in experimental mice. Single vaccination with α-galactosylceramide (αGC)-loaded A20 lymphoma cells elicited effective antitumor immunity against tumor challenge. This vaccination strategy also induced significant tumor regression in A20-bearing mice. Importantly, the survivors from primary tumor inoculation were all resistant to tumor rechallenge, indicative of established adaptive memory immunity. Depletion as well as adoptive transfer studies revealed an exclusive role of conventional CD4+ but not CD8+ T cells in mediating antitumor immunity. In addition, we found normal hematopoietic compartments in the vaccinated mice. Therefore, NKT ligand-loaded lymphoma elicits long-lasting and effective antitumor immunity, which can be further developed as patient- and tumor-specific immunotherapy against human lymphomas.</P>

Anatomic location defines antigen presentation by dendritic cells to T cells in response to intravenous soluble antigens

Chung, Yeonseok,Chang, Jae-Hoon,Kim, Byung-Seok,Lee, Jung-Mi,Kim, Ho-Youn,Kang, Chang-Yuil VCH Verlagsgesellschaft mbH, etc 2007 European journal of immunology Vol. No.

<P>In the spleen, exogenous antigen is preferentially presented by CD8&agr;<SUP>+</SUP>CD11b<SUP>–</SUP> DC to CD8 T cells and by CD8&agr;<SUP>–</SUP>CD11b<SUP>+</SUP> DC to CD4 T cells. However, it is not yet clear whether the same rule applies to other secondary lymphoid organs. To address this issue, we first classified secondary lymphoid tissues into three categories based on the expression pattern of CD8&agr; and CD11b in C57BL/6 and BALB/c mice: (a) spleen, (b) mesenteric lymph node (MLN) and (c) other peripheral lymph nodes (PLN). We then analyzed the OVA-specific T cell-stimulating capacity of each DC subset after intravenous injection with soluble OVA. Our results show that, regardless of tissue origin, CD8&agr;<SUP>–</SUP>CD11b<SUP>+</SUP> DC generally present OVA to CD4 T cells, a finding that held true as well for CD8&agr;<SUP>+</SUP>CD11b<SUP>+</SUP> DC in PLN. In striking contrast, CD8&agr;<SUP>+</SUP>CD11b<SUP>–</SUP> DC in spleen, CD8&agr;<SUP>–</SUP>CD11b<SUP>+</SUP> DC in MLN and CD8&agr;<SUP>+</SUP>CD11b<SUP>+</SUP> DC in PLN mainly cross-present OVA to CD8 T cells in their respective tissues. Of note, CD8&agr;<SUP>–</SUP>CD11b<SUP>+</SUP> DC in MLN and CD8&agr;<SUP>+</SUP>CD11b<SUP>+</SUP> DC in PLN present OVA to both CD4 T and CD8 T cells. Therefore, the antigen-presenting capacity of each distinct DC subset is determined by its anatomic environment in combination with its surface phenotype.</P>

Oral Tolerance: Not Simple But more Complex

Yeonseok Chung,Chang-Yuil Kang 대한면역학회 2003 Immune Network Vol.3 No.3

Cross-Regulation between Atherosclerosis and Autoimmunity

Yeonseok Chung 한국실험동물학회 2014 한국실험동물학회 학술발표대회 논문집 Vol.2014 No.8

Split peripheral tolerance: CD40 ligation blocks tolerance induction for CD8 T cells but not for CD4 T cells in response to intestinal antigens

Chung, Yeonseok,Ko, Sung-Youl,Ko, Hyun-Jeong,Kang, Chang-Yuil WILEY-VCH Verlag 2005 European journal of immunology Vol.35 No.5

<P>The role of antigen-presenting cells in the balance between immunity and tolerance to intestinal antigens remains poorly understood. In this study, we examined whether CD40 ligation affects the induction of CD4 and CD8 T cell tolerance in response to intestinal antigens. We show that an agonistic anti-CD40 mAb treatment did not block the induction of OVA-specific CD4 T cell tolerance, whereas this approach enabled strong priming of OVA-specific cytotoxic T cells (CTL), preventing CTL tolerance to intestinal antigen. Such CTL priming was independent of CD4 T cell help but required B7 costimulation. Co-administration of anti-CD40 mAb increased the synthesis of IL-2 and the expression of CD25 by CD8 T cells, but neither IL-2 production nor CD25 expression by CD4 T cells was enhanced by anti-CD40 mAb. However, neutralization of TGF-&bgr; together with addition of agonistic anti-CD40 mAb was able to reverse CD4 T cell tolerance. These findings suggest that the induction of tolerance versus immunity against intestinal antigens is determined by the status of the antigen-presenting cells and that signals via CD40 differently regulate the outcome of CD4 and CD8 T cells in vivo.</P>

Complementary role of CD4⁺CD25⁺regulatory T cells and TGF-β in oral tolerance

Chung, Yeonseok,Lee, Seung-Ho,Kim, Dong-Hyeon,Kang, Chang-Yuil Wiley (John WileySons) 2005 Journal of Leukocyte Biology Vol.77 No.6

<P>CD4(+)CD25(+) regulatory T cells are thought to be generated in the periphery as well as in the thymus. We sought to determine the roles played by CD4(+)CD25(+) T cells and transforming growth factor-beta (TGF-beta) in the induction and maintenance of tolerance generated by oral antigens in BALB/c mice. We found that oral administration of a high dose of ovalbumin (OVA) suppressed OVA-specific proliferation and antibody production in BALB/c mice depleted of CD25(+) cells. In contrast, the unresponsiveness induced by lower doses of OVA was only partially blocked by CD25 depletion prior to feeding. Depletion of CD4(+)CD25(+) cells after mice were orally tolerized did not reverse the tolerant status, indicating that these cells were not required to maintain the established tolerance. Furthermore, the induction of oral tolerance was not hampered by the administration of TGF-beta-neutralizing antibodies. However, in mice depleted of CD25(+) cells, anti-TGF-beta-neutralizing antibodies blocked the induction of tolerance, regardless of whether the mice followed the high- or low-dose regimens of oral OVA. CD25 depletion together with TGF-beta neutralization led the expansion of OVA-specific CD4 T cells against the subsequent antigen challenge, and each treatment alone did not. Our findings indicate that CD4(+)CD25(+) T cells and TGF-beta play a complementary role in the induction of oral tolerance, at least in part, by regulating the expansion of antigen-specific CD4 T cells.</P>

Oral Tolerance: Not Simple But more Complex

Chung, Yeonseok,Kang, Chang-Yuil The Korean Association of Immunobiologists 2003 Immune Network Vol.3 No.3

The intestinal immune system can discriminate between harmful and unharmful antigens and do not provoke productive immunity to unharmful antigen. Thus oral administration of antigen is one of classical methods for inducing antigen-specific immune tolerance in the periphery. Furthermore, oral tolerance has been investigated for the treatment of autoimmune disorders in human clinical trials. However, the detail mechanism of oral tolerance and contributing factors are not defined clearly at this time. Recent studies demonstrate unique types of immune cell that suppressing immune response, such as regulatory T cell and tolerogenic dendritic cell. This article reviews the factors involved in oral tolerance and discusses our current understanding base on the recent literatures and our works.

Cellular and Molecular Links between Autoimmunity and Lipid Metabolism

Yeonseok Chung,류희주,김지연,김대홍,이정은 한국분자세포생물학회 2019 Molecules and cells Vol.42 No.11

The incidence of atherosclerosis is higher among patients with several autoimmune diseases such as psoriasis, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). It is well documented that innate immune cells including macrophages and dendritic cells sense lipid species such as saturated fatty acids and oxidized low-density lipoprotein and produce pro-inflammatory cytokines and chemokines. However, whether a hyperlipidemic environment also impacts autoimmune T cell responses has been unclear. Among CD4+ T cells, Th17 and follicular helper T (Tfh) cells are known to play pathogenic roles in the development of hyperlipidemiaassociated autoimmune diseases. This review gives an overview of the cellular and molecular mechanisms by which dysregulated lipid metabolism impacts the pathogenesis of autoimmune diseases, with specific emphasis on Th17 and Tfh cells.

Blockade of STAT3 in T Cells Inhibits Germinal Center Reactions against Intranasal Allergens

Choi, Garam,Chung, Yeonseok The Korean Society of Applied Pharmacology 2016 Biomolecules & Therapeutics(구 응용약물학회지) Vol.24 No.3

Understanding the developmental mechanisms of humoral immunity against intranasal antigens is essential for the development of therapeutic approaches against air-borne pathogens as well as allergen-induced pulmonary inflammation. Follicular helper T (Tfh) cells expressing CXCR5 are required for humoral immunity by providing IL-21 and ICOS costimulation to activated B cells. However, the regulation of Tfh cell responses against intranasal antigens remains unclear. Here, we found that the generation of Tfh cells and germinal center B cells in the bronchial lymph node against intranasal proteinase antigens was independent of $TGF-{\beta}$. In contrast, administration of STAT3 inhibitor STA-21 suppressed the generation of Tfh cells and germinal center B cells. Compared with wild-type OT-II T cells, STAT3-deficient OT-II T cells transferred into recipients lacking T cells not only showed significantly reduced frequency Tfh cells, but also induced diminished IgG as well as IgE specific for the intranasal antigens. Cotransfer study of wild-type OT-II and STAT3-deficient OT-II T cells revealed that the latter failed to differentiate into Tfh cells. These findings demonstrate that T cell-intrinsic STAT3 is required for the generation of Tfh cells to intranasal antigens and that targeting STAT3 might be an effective approach to ameliorate antibody-mediated pathology in the lung.

Dyslipidemia promotes germinal center reactions via IL-27

( Heeju Ryu ),( Yeonseok Chung ) 생화학분자생물학회(구 한국생화학분자생물학회) 2018 BMB Reports Vol.51 No.8

Cardiovascular disease such as atherosclerosis is caused by imbalanced lipid metabolism and represents a leading cause of death worldwide. Epidemiological studies show that patients with systemic autoimmune diseases exhibit a higher incidence of atherosclerosis. Conversely, hyperlipidemia has been known to accelerate the incidence of autoimmune diseases in humans and in animal models. However, there is a considerable gap in our understanding of how atherosclerosis impacts the development of the autoimmunity in humans, and vice versa. The atherosclerosis-related autoimmune diseases include psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE) and diabetes mellitus. By using animal models of atherosclerosis and SLE, we have recently demonstrated that hyperlipidemia significantly accelerates the development of autoantibodies, by inducing autoimmune follicular helper T (T_FH) cells. Mechanistic studies have identified that hyperlipidemia induces IL-27 production in a TLR4-dependent manner, likely via downregulating LXR expression in dendritic cells. In this case, mice lacking IL-27 do not develop enhanced antibody responses. Thus it is noted that these findings propose a mechanistic insight responsible for the tight association between cardiovascular diseases and SLE in humans. [BMB Reports: Perspective 2018; 51(8): 371-372]