Regulatory T cells (Tregs) are engaged in maintaining immune homeostasis and preventing autoimmunity. Treg cells include thymic Treg cells and peripheral Treg cells, both of which can suppress the ...immune response via multiple distinct mechanisms. The differentiation, proliferation, suppressive function and survival of Treg cells are affected by distinct energy metabolic programs. Tissue-resident Treg cells hold unique features in comparison with the lymphoid organ Treg cells. Foxp3 transcription factor is a lineage master regulator for Treg cell development and suppressive activity. Accumulating evidence indicates that the activity of Foxp3 protein is modulated by various post-translational modifications (PTMs), including phosphorylation, O-GlcNAcylation, acetylation, ubiquitylation and methylation. These modifications affect multiple aspects of Foxp3 function. In this review, we define features of Treg cells and roles of Foxp3 in Treg biology, and summarize current research in PTMs of Foxp3 protein involved in modulating Treg function. This review also attempts to define Foxp3 dimer modifications relevant to mediating Foxp3 activity and Treg suppression. Understanding Foxp3 protein features and modulation mechanisms may help in the design of rational therapies for immune diseases and cancer.
Regulatory T cells (Tregs) are a subpopulation of T cells that are specialized in suppressing immune responses. Here we show that the arginine methyl transferase protein PRMT5 can complex with FOXP3 ...transcription factors in Tregs. Mice with conditional knock out (cKO) of PRMT5 expression in Tregs develop severe scurfy-like autoimmunity. In these PRMT5 cKO mice, the spleen has reduced numbers of Tregs, but normal numbers of Tregs are found in the peripheral lymph nodes. These peripheral Tregs that lack PRMT5, however, display a limited suppressive function. Mass spectrometric analysis showed that FOXP3 can be di-methylated at positions R27, R51, and R146. A point mutation of Arginine (R) 51 to Lysine (K) led to defective suppressive functions in human CD4 T cells. Pharmacological inhibition of PRMT5 by DS-437 also reduced human Treg functions and inhibited the methylation of FOXP3. In addition, DS-437 significantly enhanced the anti-tumor effects of anti-erbB2/neu monoclonal antibody targeted therapy in Balb/c mice bearing CT26Her2 tumors by inhibiting Treg function and induction of tumor immunity. Controlling PRMT5 activity is a promising strategy for cancer therapy in situations where host immunity against tumors is attenuated in a FOXP3 dependent manner.
Ricardo and International Trade Senga, Shigeyoshi; Fujimoto, Masatomi; Tabuchi, Taichi
2017, 20170518, 2017-05-18, Letnik:
195
eBook
iDavid Ricardo’s theories have been widely studied and discussed, including the prominent theory on comparative advantage. Ricardo and International Trade looks at the ongoing renaissance of the ...Ricardian international trade theory. The book’s interpretation brings fresh insights into and new developments on the Ricardian international trade theory by examining the true meaning of the ‘four magic numbers’. By putting together theories of comparative advantage and international money, the book attempts to elucidate Ricardo’s international trade theory in the real world.
This book also features contributions from the Japanese perspective and compares Ricardian theories with those of his contemporaries, such as Malthus, Torrens and J. S. Mill. This book will be a valuable reference for researchers and scholars with interests in history of economic thought and international economics.ii
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Natural killer (NK) cells recognize tumor cells and virus-infected cells and attack without being sensitized to antigens. The development of the antitumor/antivirus activities of NK cells is ...controlled by multiple mechanisms such as direct cytotoxic activity against target cells, antibody-dependent cell-mediated cytotoxicity, secretion of Th1-type cytokines, and interactions with dendritic cells. The development of these activities plays a significant role in both innate and adaptive immunities. Considering the recent progress made in elucidating the molecular and cellular biology of NK cells, we summarize the current situation and discuss future possibilities with regard to NK cell-based adoptive immunotherapy.
Background Injecting various protein antigens conjugated to monomethoxypolyethylene glycol (mPEG) results in antigen-specific tolerance to subsequent immunization. In the present study the ability of ...mPEG-modified cardiac myosin (CM) to block the development of experimental autoimmune myocarditis (EAM) induced by CM immunization or by the transfer of lymphocytes from CM-immunized donors was studied. Methods and Results A/J mice were injected with mPEG-CM before active or passive EAM induction. We examined the suppressive mechanism by the transfer of lymphocytes from mPEG-CM-treated mice into naïve mice. To ascertain the cells responsible for suppressing EAM induction, in vivo or in vitro depletion of CD4+ or CD8+ T cells was performed. mPEG-CM administered before active or passive EAM induction markedly suppressed the incidence and severity of EAM and reduced CM-specific antibody responses. When lymphocytes from mPEG-CM treated mice were transferred into naïve mice that were then immunized with CM, the suppressive effect was recapitulated. Conclusions mPEG-CM treatment blocked the active and passive induction of EAM. (Circ J 2004; 68: 149 - 155)
The protective effects of bacteriophages were assessed against experimental Staphylococcus aureus infection in mice. Of the S. aureus phages isolated in the study, ϕMR11 was representatively used for ...all testing, because its host range was the most broad and it carries no genes for known toxins or antibiotic resistance. Intraperitoneal injections (8×108 cells) of S. aureus including methicillin-resistant bacteria, caused bacteremia and eventual death in mice. In contrast, subsequent intraperitoneal administration of purified ϕMR11 (MOI ⩾0.1) suppressed S. aureus–induced lethality. This lifesaving effect coincided with the rapid appearance of ϕMR11 in the circulation, which remained at substantial levels until the bacteria were eradicated. Inoculation with high-dose ϕMR11 alone produced no adverse effects attributable to the phage. These results uphold the efficacy of phage therapy against pernicious S. aureus infections in humans and suggest that ϕMR11 may be a potential prototype for gene-modified, advanced therapeutic S. aureus phages
We have found suppressor T cells that inhibit the proliferative response of naive CD4 + T cells in T cell receptor (TCR) Vβ8.1 transgenic mice rendered tolerant in vivo by inoculation of Mls-1 a ...-positive cells. This suppression was mediated by CD4 + T cells but not by CD8 + T cells or double-negative (DN) cells, and splenic CD4 + T cells from tolerant mice displayed a greater suppression than lymph node CD4 + T cells. Cell contact was required for efficient suppression, and known inhibitory cytokines such as IL-4, IL-10, and transforming growth factor β were not involved. Suppressor T cells inhibited IL-2 production by naive CD4 + T cells, and the addition of exogenous IL-2 diminished the suppressed activity while having little activity on tolerant T cells. Suppression was abolished by the elimination of CD25 + T cells in the tolerant CD4 + T cell subset. CD25 + CD4 + T cells suppressed the proliferative response of the residual fraction of the nonanergic population, namely, 6C10 + CD4 + T cells still present in the tolerant mice. However, 6C10 − CD4 + T cells still had reduced reactivity to Mls-1 a even after CD25 + CD4 + T cells were removed and exogenous IL-2 was added. Suppressor cells appear to affect only residual nonanergic cells in situ , thereby facilitating the maintenance of the unresponsive state in vivo . These data provide a framework for understanding suppressor T cells and explain the difficulties and variables in defining their activity in other systems, because suppressor T cells apparently control only a small population of nonanergic cells in the periphery and may be viewed as a homeostatic mechanism.
We investigated the type of T cell response involved in Meth A tumor rejection in primary immune and hyperimmune syngeneic mice. It was found that a CD4+ T cell‐mediated delayed‐type hypersensitivity ...(DTH) response activating non‐specific killer cells such as macrophages, NK and LAK cells, without a specific CD8+ cytotoxic T lymphocyte (CTL) response, was the major immune response leading to Meth A tumor rejection in primary immune mice. In contrast, the specific CD8+ CTL response was the major response leading to the tumor rejection, in addition to CD4+ T cell‐mediated DTH response, in hyperimmune mice. Analysis of CD4+ T cell clones established from primary immune and hyperimmune spleen cells indicated that a CD4+ T cell clone (C9) of primary immune mice (although only one clone was established) was of Th1 type, and induced cytotoxicity in accessory cells by classic DTH in vitro. Eight CD4+ T cell clones were established from hyperimmune spleen cells. Six out of the eight clones were of the Th2 type and two were Th0‐like. However, no Th1‐type CD4+ T cell clone was established from hyperimmune spleen cells. All of these CD4+ T cell clones, even the Th2‐type clones, were capable of inducing cytotoxicity in vitro in T cell‐depleted accessory cells, as in an in vitro DTH response. We postulate on the basis of these results that the T cell response leading to Meth A tumor rejection in vivo sequentially changed from a CD4+ T cell‐mediated classic DTH response to a CD8+ CTL response, in addition to a cellular response mediated probably by Th2‐type cells, during the process of repeated immunization.
Regulatory T cells (Tregs) are a subpopulation of T cells that are specialized in suppressing immune responses. Here we show that the arginine methyl transferase protein PRMT5 can complex with FOXP3 ...transcription factors in Tregs. Mice with conditional knock out (cKO) of PRMT5 expression in Tregs develop severe scurfy-like autoimmunity. In these PRMT5 cKO mice, the spleen has reduced numbers of Tregs, but normal numbers of Tregs are found in the peripheral lymph nodes. These peripheral Tregs that lack PRMT5, however, display a limited suppressive function. Mass spectrometric analysis showed that FOXP3 can be di-methylated at positions R27, R51, and R146. A point mutation of Arginine (R) 51 to Lysine (K) led to defective suppressive functions in human CD4 T cells. Pharmacological inhibition of PRMT5 by DS-437 also reduced human Treg functions and inhibited the methylation of FOXP3. In addition, DS-437 significantly enhanced the anti-tumor effects of anti-erbB2/neu monoclonal antibody targeted therapy in Balb/c mice bearing CT26Her2 tumors by inhibiting Treg function and induction of tumor immunity. Controlling PRMT5 activity is a promising strategy for cancer therapy in situations where host immunity against tumors is attenuated in a FOXP3 dependent manner.
Over-expression of cellular protooncogenes has been proposed to function in the initiation and maintenance of malignancies. In order to distinguish malignant lymphoma from reactive proliferative ...diseases, we surveyed the expression levels of three protooncogenes(c-myc, c-fos and c-myb) in malignant lymphoma and reactive proliferative diseases. An increased level of c-myc or c-fos mRNA was observed in one case, respectively, out of three malignant lymphomata. The other cases exhibited no enhancement in protooncogenes. These oncogenes are critically regulated during differentiation, but the half-life of c-myc mRNA was very short, and the level of the mRNA decreased to the initial level very quickly. Thus, the high level of the expression of these oncogenes may not always be maintained in all malignant cells. We then examined the level of mRNA for poly(ADP-ribose) synthetase in those cases. An enhanced expression for the synthetase gene was observed in all five malignant lymphomata tested, but no increase in the level of the mRNA was observed in any reactive proliferative cases or normal lymph nodes. These results suggest that enhanced expression of poly(ADP-ribose) synthetase gene seems to be a common characteristic of protopathic malignant lymphoma. By using the characteristics of malignant lymphoma, the level of mRNA for the synthetase may be applicable for differential diagnosis of malignant lymphoma from several pathologically indistinguishable diseases.
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