Although forkhead box p3 (Foxp3) expression is restricted to naturally occurring CD4+ regulatory T cells (TREG), little is known about the various signals that regulate it in T cells. As TGF‐β has ...been reported to modulate Foxp3 expression in T cells, we investigated its effects on the induction or maintenance of regulatory functions in different CD4+ T cell subsets. TGF‐β1 priming was able to promote differentiation of TREG cells from nonregulatory CD4+CD25– T cells in a concentration‐dependent manner through Foxp3 induction. As CD4+CD25– T cells remain a highly heterogeneous population with variable degrees of antigen experience, we then examined the effect of TGF‐β1 on naive CD4+CD25–CD45RBHIGH T cells. Freshly isolated or TGF‐β1‐treated CD4+CD25–CD45RBHIGH T cells never displayed any regulatory functions or significant Foxp3 expression following TCR activation. In stark contrast, freshly isolated CD4+CD25–CD45RBLOW cells, albeit expressing low levels of Foxp3 mRNA and protein, were unable to suppress CD4+ effector T cell proliferation but acquired regulatory activity and de novo Foxp3 expression following TGF‐β1 exposure. Furthermore, suppression was IL‐10‐dependent, as anti‐IL‐10 receptor antibody treatment abrogated this suppression completely, consistent with the ability of TGF‐β1‐treated CD4+CD25–CD45RBLOW to synthesize IL‐10 upon restimulation in vitro. Last, we show that TGF‐β1 treatment or blockade did not lead to enhanced expansion or function of naturally occurring CD4+CD25+ TREG cells, although it maintained Foxp3 mRNA and protein expression. Altogether, TGF‐β1 promotes the induction of IL‐10‐secreting CD4+ TREG cells from CD4+CD25–CD45RBLOW precursors through de novo Foxp3 production and maintains natural TREG cell peripheral homeostasis by sustaining Foxp3 expression.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The neonatal crystallizable fragment receptor (FcRn) functions as an intracellular protection receptor for immunoglobulin G (IgG). Recently, several clinical studies have reported the lowering of ...circulating monomeric IgG levels through FcRn blockade for the potential treatment of autoimmune diseases. Many autoimmune diseases, however, are derived from the effects of IgG immune complexes (ICs). We generated, characterized, and assessed the effects of SYNT001, a FcRn-blocking monoclonal antibody, in mice, nonhuman primates (NHPs), and humans. SYNT001 decreased all IgG subtypes and IgG ICs in the circulation of humans, as we show in a first-in-human phase 1, single ascending dose study. In addition, IgG IC induction of inflammatory pathways was dependent on FcRn and inhibited by SYNT001. These studies expand the role of FcRn in humans by showing that it controls not only IgG protection from catabolism but also inflammatory pathways associated with IgG ICs involved in a variety of autoimmune diseases.
: Nonobese diabetic (NOD) mice serve as a model of spontaneous type 1 diabetes (T1D), a T cell‐mediated autoimmune disease leading to the destruction of pancreatic insulin‐producing beta islet cells. ...A possible deficiency in regulatory T (Treg) cell development or function may promote the activation, expansion, and recruitment of autoreactive T cells and the onset of T1D. Naturally occurring CD4+CD25+ Treg (nTreg) cells, which typically display potent inhibitory effects on T cell functions in vitro and in vivo, may be defective at controlling autoimmunity in T1D. We have examined the relative contribution of CD4+CD25+ nTreg cells in the immune regulation of T1D in the NOD mouse model. CD4+CD25+ T cells represent 5‐10% of CD4+ thymocytes or peripheral T cells from prediabetic neonatal NOD mice, are anergic to TCR signals, and potently suppress activated T cells in a contact‐dependent and cytokine‐independent fashion in vitro. Unlike total CD4+ T cells, prediabetic CD25+‐depleted CD4+ T cells are potently diabetogenic when transferred in immunodeficient NOD mice. Co‐transfer of CD4+CD25+ T cells from thymocytes or peripheral lymphoid tissues of neonatal NOD mice dramatically halts disease development and beta‐islet cell lymphocytic infiltration, even when T1D is induced by CD4+ T cells from BDC2.5 transgenic or diabetic NOD mice. Finally, we show that CD4+CD25+ Treg preferentially accumulate in inflamed pancreatic environments, where they potently inhibit the antigen‐specific expansion and cytokine effector functions of diabetogenic T cells. Thus, CD4+CD25+ T cell‐mediated regulation is operative in the prediabetic neonatal T cell repertoire and can suppress the diabetogenic process and control the onset of T1D.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Although forkhead box p3 (Foxp3) expression is restricted to naturally occurring CD4(+) regulatory T cells (T(REG)), little is known about the various signals that regulate it in T cells. As TGF-beta ...has been reported to modulate Foxp3 expression in T cells, we investigated its effects on the induction or maintenance of regulatory functions in different CD4(+) T cell subsets. TGF-beta1 priming was able to promote differentiation of T(REG) cells from nonregulatory CD4(+)CD25(-) T cells in a concentration-dependent manner through Foxp3 induction. As CD4(+)CD25(-) T cells remain a highly heterogeneous population with variable degrees of antigen experience, we then examined the effect of TGF-beta1 on naive CD4(+)CD25(-)CD45RB(HIGH) T cells. Freshly isolated or TGF-beta1-treated CD4(+)CD25(-)CD45RB(HIGH) T cells never displayed any regulatory functions or significant Foxp3 expression following TCR activation. In stark contrast, freshly isolated CD4(+)CD25(-)CD45RB(LOW) cells, albeit expressing low levels of Foxp3 mRNA and protein, were unable to suppress CD4(+) effector T cell proliferation but acquired regulatory activity and de novo Foxp3 expression following TGF-beta1 exposure. Furthermore, suppression was IL-10-dependent, as anti-IL-10 receptor antibody treatment abrogated this suppression completely, consistent with the ability of TGF-beta1-treated CD4(+)CD25(-)CD45RB(LOW) to synthesize IL-10 upon restimulation in vitro. Last, we show that TGF-beta1 treatment or blockade did not lead to enhanced expansion or function of naturally occurring CD4(+)CD25(+) T(REG) cells, although it maintained Foxp3 mRNA and protein expression. Altogether, TGF-beta1 promotes the induction of IL-10-secreting CD4(+) T(REG) cells from CD4(+)CD25(-)CD45RB(LOW) precursors through de novo Foxp3 production and maintains natural T(REG) cell peripheral homeostasis by sustaining Foxp3 expression.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract The complex interaction between natural killer (NK) cells and cytomegalovirus is a paradigm of the co-evolution between genomes of large DNA viruses and their host immune systems. Both human ...and mouse cytomegalovirus posses numerous mechanisms to avoid NK cell detection. Linkage studies, positional cloning and functional studies in mice and cells, have led to the identification of key genes governing resistance to cytomegalovirus, including various NK cell activating receptors of major histocompatibility complex (MHC) class I. These receptors, however, seem to require either viral or host MHC class I molecules to operate recognition and elimination of the cytomegalovirus-infected cell leading to host resistance. Here we will review the genes and molecules involved in these mechanisms while contrasting their function with that of other NK cell receptors. Activating receptors of MHC class I may represent a window of therapeutic intervention during human infection with viruses, of which cytomegalovirus remains an important health threat.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Although forkhead box p3 (Foxp3) expression is restricted to naturally occurring CD4 super(+) regulatory T cells (Treg), little is known about the various signals that regulate it in T cells. As TGF- ...beta has been reported to modulale Foxp3 expression in T cells, we investigated its effects on the induction or maintenance of regulatory functions in different CD4 super(+) T cell subsets. TGF- beta 1 priming was able to promote differentiation of Treg cells from nonregulatory CD4 super(+)CD25 super(-) T cells in a concentration-dependent manner through Foxp3 induction. As CD4 super(+)CD25 super(-) T cells remain a highly heterogeneous population with variable degrees of antigen experience, we then examined the effect of TGF- beta 1 on naive CD4 super(+)CD25 super(-) CD45RB super(HIGH) T cells. Freshly isolated or TGF- beta 1 -treated CD4 super(+)CD25 super(-)CD45RB super(HIGH) T cells never displayed any regulatory functions or significant Foxp3 expression following TCR activation. In stark contrast, freshly isolated CD4 super(+)CD25 super(-)CD45RB super(LOW) cells, albeit expressing low levels of Foxp3 mRNA and protein, were unable to suppress CD4 super(+) effector T cell proliferation but acquired regulatory activity and de novo Foxp3 expression following TGF- beta 1 exposure. Furthermore, suppression was IL-10-dependent, as anti-IL-10 receptor antibody treatment abrogated this suppression completely, consistent with the ability of TGF- beta 1 -treated CD4 super(+)CD25 super(-)CD45RB super(LOW) to synthesize IL-10 upon restimulation in vitro. Last, we show that TGF- beta 1 treatment or blockade did not lead to enhanced expansion or function of naturally occurring CD4 super(+)CD25 super(+) Treg cells, although it maintained Foxp3 mRNA and protein expression. Altogether, TGF- beta 1 promotes the induction of IL-10-secreting CD4 super(+) Treg cells from CD4 super(+)CD25 super(-)CD45RB super(LOW) precursors through de novo Foxp3 production and maintains natural Treg cell peripheral homeostasis by sustaining Foxp3 expression.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Genetically distinct inbred strains of mice that differ in their susceptibility to mouse cytomegalovirus (MCMV) are invaluable for dissecting complex host–pathogen interactions. Their study has ...allowed the identification of host-resistance loci, including several activating NK cell receptors of major histocompatibility complex (MHC) class I. In this chapter, we provide a practical guide to the genetic mapping and functional characterization of NK cell receptors that control innate immunity against MCMV via specific recognition of infected cells.
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FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Modern diets are largely heat-processed and as a result contain high levels of advanced glycation end products (AGEs). Dietary advanced glycation end products (dAGEs) are known to contribute to ...increased oxidant stress and inflammation, which are linked to the recent epidemics of diabetes and cardiovascular disease. This report significantly expands the available dAGE database, validates the dAGE testing methodology, compares cooking procedures and inhibitory agents on new dAGE formation, and introduces practical approaches for reducing dAGE consumption in daily life. Based on the findings, dry heat promotes new dAGE formation by >10- to 100-fold above the uncooked state across food categories. Animal-derived foods that are high in fat and protein are generally AGE-rich and prone to new AGE formation during cooking. In contrast, carbohydrate-rich foods such as vegetables, fruits, whole grains, and milk contain relatively few AGEs, even after cooking. The formation of new dAGEs during cooking was prevented by the AGE inhibitory compound aminoguanidine and significantly reduced by cooking with moist heat, using shorter cooking times, cooking at lower temperatures, and by use of acidic ingredients such as lemon juice or vinegar. The new dAGE database provides a valuable instrument for estimating dAGE intake and for guiding food choices to reduce dAGE intake.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Nonobese diabetic (NOD) mice serve as a model of spontaneous type 1 diabetes (T1D), a T cell-mediated autoimmune disease leading to the destruction of pancreatic insulin-producing beta islet cells. A ...possible deficiency in regulatory T (T sub(reg)) cell development or function may promote the activation, expansion, and recruitment of autoreactive T cells and the onset of T1D. Naturally occurring CD4 super(+)CD25 super(+) T sub(reg) (nT sub(reg)) cells, which typically display potent inhibitory effects on T cell functions in vitro and in vivo, may be defective at controlling autoimmunity in T1D. We have examined the relative contribution of CD4 super(+)CD25 super(+) nT sub(reg) cells in the immune regulation of T1D in the NOD mouse model. CD4 super(+)CD25 super(+) T cells represent 5-10% of CD4 super(+) thymocytes or peripheral T cells from prediabetic neonatal NOD mice, are anergic to TCR signals, and potently suppress activated T cells in a contact-dependent and cytokine-independent fashion in vitro. Unlike total CD4 super(+) T cells, prediabetic CD25 super(+)-depleted CD4 super(+) T cells are potently diabetogenic when transferred in immunodeficient NOD mice. Co-transfer of CD4 super(+)CD25 super(+) T cells from thymocytes or peripheral lymphoid tissues of neonatal NOD mice dramatically halts disease development and beta-islet cell lymphocytic infiltration, even when T1D is induced by CD4 super(+) T cells from BDC2.5 transgenic or diabetic NOD mice. Finally, we show that CD4 super(+)CD25 super(+) T sub(reg) preferentially accumulate in inflamed pancreatic environments, where they potently inhibit the antigen-specific expansion and cytokine effector functions of diabetogenic T cells. Thus, CD4 super(+)CD25 super(+) T cell-mediated regulation is operative in the prediabetic neonatal T cell repertoire and can suppress the diabetogenic process and control the onset of T1D.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Eight untrained men performed 15-s and 60-s high-intensity exercise on a bicycle ergometer. Activities of the creatine kinase (CK) and lactate dehydrogenase (LDH) were measured in blood 3 min and 2, ...6, and 24 h after cessation of exercise. The results indicate that anaerobic exercise induces a transient increase in plasma LDH activity and a more prolonged elevation in plasma CK activity. A negative correlation was found between CK activity measured before and 3 min after exercise and mean power, and total external work performed in both test types. A similar correlation was ascertained between pre- and post-exercise CK activity and maximal power output measured in the 60-s test. After the 15-s exercise test, only post-exercise plasma CK activity was negatively correlated with the maximal power output.
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