Role of T regulatory suppression in autoimmunity and cancer

最近已经清楚的是，T细胞的一个子集，如CD4+CD25+FoxP3+T调节（Treg）细胞在维持免疫稳态中是必不可少的，并对免疫反应具有反馈抑制作用。据报道，这些Treg细胞抑制自身免疫反应，因此，不幸的是，也保护肿瘤免受免疫排斥。我们的观察表明，基因不同的小鼠品系对自身免疫和癌症的易感性可能是由Tregs的数量和抑制活性决定的。我们之前的研究表明，用于治疗自身免疫性疾病的免疫抑制剂地塞米松（dexamethasone， DEX）和淋巴细胞增殖性细胞因子白细胞介素-2 （Interleukin-2）各自上调小鼠Treg细胞的数量。此外，当它们一起使用时，在促进免疫抑制性Treg细胞活性方面有更大的作用。当在诱导实验性自身免疫性脑脊髓炎（EAE）的抗原（MOG）之前一起给药时，IL-2加DEX降低了易感小鼠EAE的发生率和严重程度。因此，可的松衍生物对Tregs的上调可以抵消自身免疫性疾病的诱导。百日咳毒素（PTX）作为佐剂与适当的自身抗原在完全弗氏佐剂（CFA）中共同给药，以诱导易感小鼠菌株的EAE。这与功能性Treg细胞数量的减少和PTX伴随的TLR4激活有关。我们确定PTX也有诱导DC产生高水平IL-6的能力。这与共同产生的TGFbeta一起导致TH17途径的激活，大量产生IL-17，这与促进多种自身免疫性疾病有关。因此，我们计划通过在治疗性抗癌疫苗中使用PTX来研究其相当独特的多重辅助作用对克服肿瘤耐受性的影响。在本财政年度，我的小组发现了一种免疫抑制药物雷帕霉素，与环孢素A不同，它也促进功能性treg的产生，同时抑制Th17细胞的分化。因此，它是一种很好的治疗自身免疫性疾病，但可能促进肿瘤生长。最后，让我们惊讶的是，我们对各种细胞因子和警报器对Treg的影响的研究表明，TNF也是Treg数量和活性的有效上调因子。尽管TNF是一种众所周知的促炎细胞因子，它对T输出细胞具有初始激活作用，但在体外和体内小鼠免疫应答过程中，尤其是作为IL-2的共刺激物，TNF诱导优先表达TNFR2受体的功能性Treg细胞的增殖扩增。IL-1和IL-6都没有这种双相作用。因此，TNF似乎在免疫应答中诱导了一种独特的延迟下调作用。这在TNFR2敲除小鼠中是不存在的，这可能解释了它们较不严重（致命）的败血症（LPS）诱导的炎症反应。我们进一步研究了TNFR2在treg中的作用，以及肿瘤通过产生TNF可能促进treg浸润肿瘤的增加，从而降低肿瘤免疫反应的可能性。我们发现TNFR2+ Tregs （CD4+CD25+FOXP3+）比TNFR2-Tregs具有更强的抑制作用。肿瘤浸润性T细胞主要由超抑制性treg组成，这些treg抑制宿主T效应细胞对肿瘤的免疫反应。许多肺和乳腺肿瘤及其浸润性白细胞已被证明可产生TNF。初步研究表明，抑制TNF-TNFR2相互作用与肿瘤生长显著降低有关。最近已经清楚的是，T细胞的一个子集，如CD4+CD25+FoxP3+T调节（Treg）细胞在维持免疫稳态中是必不可少的，并对免疫反应具有反馈抑制作用。据报道，这些Treg细胞抑制自身免疫反应，因此，不幸的是，也保护肿瘤免受免疫排斥。我们的观察表明，基因不同的小鼠品系对自身免疫和癌症的易感性可能是由Tregs的数量和抑制活性决定的。我们之前的研究表明，用于治疗自身免疫性疾病的免疫抑制剂地塞米松（dexamethasone， DEX）和淋巴细胞增殖性细胞因子白细胞介素-2 （Interleukin-2）各自上调小鼠Treg细胞的数量。此外，当它们一起使用时，在促进免疫抑制性Treg细胞活性方面有更大的作用。当在诱导实验性自身免疫性脑脊髓炎（EAE）的抗原（MOG）之前一起给药时，IL-2加DEX降低了易感小鼠EAE的发生率和严重程度。因此，可的松衍生物对Tregs的上调可以抵消自身免疫性疾病的诱导。百日咳毒素（PTX）作为佐剂与适当的自身抗原在完全弗氏佐剂（CFA）中共同给药，以诱导易感小鼠菌株的EAE。这与功能性Treg细胞数量的减少和PTX伴随的TLR4激活有关。我们确定PTX也有诱导DC产生高水平IL-6的能力。这与共同产生的TGFbeta一起导致TH17途径的激活，大量产生IL-17，这与促进多种自身免疫性疾病有关。因此，我们计划通过在治疗性抗癌疫苗中使用PTX来研究其相当独特的多重辅助作用对克服肿瘤耐受性的影响。在本财政年度，我的小组发现了一种免疫抑制药物雷帕霉素，与环孢素A不同，它也促进功能性treg的产生，同时抑制Th17细胞的分化。因此，它是一种很好的治疗自身免疫性疾病，但可能促进肿瘤生长。最后，让我们惊讶的是，我们对各种细胞因子和警报器对Treg的影响的研究表明，TNF也是Treg数量和活性的有效上调因子。尽管TNF是一种众所周知的促炎细胞因子，它对T输出细胞具有初始激活作用，但在体外和体内小鼠免疫应答过程中，尤其是作为IL-2的共刺激物，TNF诱导优先表达TNFR2受体的功能性Treg细胞的增殖扩增。IL-1和IL-6都没有这种双相作用。因此，TNF似乎在免疫应答中诱导了一种独特的延迟下调作用。这在TNFR2敲除小鼠中是不存在的，这可能解释了它们较不严重（致命）的败血症（LPS）诱导的炎症反应。我们进一步研究了TNFR2在treg中的作用，以及肿瘤通过产生TNF可能促进treg浸润肿瘤的增加，从而降低肿瘤免疫反应的可能性。我们发现TNFR2+ Tregs （CD4+CD25+FOXP3+）比TNFR2-Tregs具有更强的抑制作用。肿瘤浸润性T细胞主要由超抑制性treg组成，这些treg抑制宿主T效应细胞对肿瘤的免疫反应。许多肺和乳腺肿瘤及其浸润性白细胞已被证明可产生TNF。Prel[截断为7800个字符的摘要]

It has recently become clear that a subset of T cells e.g. CD4+CD25+FoxP3+T regulatory (Treg) cells are essential in the maintenance of immune homeostasis and have feedback suppressive effects on immune responses. These Treg cells have been reported to suppress autoimmune responses and consequently, unfortunately, also protect tumors from immune rejection. Our observation suggested that the susceptibility to autoimmunity and cancer in genetically different mouse strains might be determined by the number and suppressive activity of Tregs. We previously showed that the immunosuppressive agent dexamethasone (DEX), which is used to treat autoimmune disease and the lymphoproliferative cytokine Interleukin-2, each upregulated the number of Treg cells in mice. Furthermore, when administered together they had even greater effects in promoting immunosuppressive Treg cell activities. When administered together prior to an antigen (MOG) that induces experimental autoimmune encephalomyelitis (EAE), IL-2 plus DEX reduced the incidence and severity of EAE in susceptible mice. Thus, upregulation of Tregs by cortisone-derivatives can counteract induction of autoimmune disease. Pertussis toxin (PTX) is coadministered as an adjuvant along with an appropriate autoantigen in Complete Freunds adjuvant (CFA) in order to induce EAE in susceptible mouse strains. This was associated with a decrease in the number of functional Treg cells and concomitant activation of TLR4 by PTX. We established that PTX also has the capacity to induce DC to produce high levels of IL-6. This leads, in conjunction with coproduced TGFbeta, to the activation of the TH17 pathway with copious production of IL-17, which has been implicated in promoting a variety of autoimmune diseases. Thus, we plan to investigate the effect of the rather unique multiplicity of adjuvant effects of PTX on overcoming tolerance to tumor by using it in therapeutic anticancer vaccines. In the current fiscal year my group showed that an immunosuppressive drug, Rapamycin, unlike cyclosporine A, also promotes the generation of functional Tregs, while inhibiting differentiation of Th17 cells. It is therefore a good therapy for autoimmune diseases, but may promote tumor growth. Finally, to our surprise our studies of the effects of various cytokines and alarmins on Tregs revealed that TNF also is a potent upregulator of Treg numbers and activity. Although TNF is a well known proinflammatory cytokine, which has initial activating effects on T efferent cells, later during in vitro and in vivo mouse immune responses especially as a costimulant with IL-2, TNF induces the proliferative expansion of functional Treg cells that preferentially express the TNFR2 receptor. Neither IL-1 nor IL-6 had such biphasic effects. Thus, TNF appears to induce a unique delayed down-regulatory effect on immune responses. This is absent in TNFR2 knockout mice and may account for their less severe (lethal) sepsis (LPS) induced inflammatory reactions. We have further investigated the role of TNFR2 on Tregs and the possibility that tumors by producing TNF may be promoting the increase in Tregs infiltrating tumors with consequent down- regulation of tumor immune responses. We have found that TNFR2+ Tregs (CD4+CD25+FOXP3+) are much more suppressive than TNFR2-Tregs. Tumor infiltrating T cells consist largely of super-suppressive Tregs that inhibit host immune responses to the tumor by T effector cells. A number of lung and breast tumors and their infiltrating leukocytes have been shown to produce TNF. Preliminary studies show that inhibition of interaction of TNF-TNFR2 is associated with a notable decrease in tumor growth.It has recently become clear that a subset of T cells e.g. CD4+CD25+FoxP3+T regulatory (Treg) cells are essential in the maintenance of immune homeostasis and have feedback suppressive effects on immune responses. These Treg cells have been reported to suppress autoimmune responses and consequently, unfortunately, also protect tumors from immune rejection. Our observation suggested that the susceptibility to autoimmunity and cancer in genetically different mouse strains might be determined by the number and suppressive activity of Tregs. We previously showed that the immunosuppressive agent dexamethasone (DEX), which is used to treat autoimmune disease and the lymphoproliferative cytokine Interleukin-2, each upregulated the number of Treg cells in mice. Furthermore, when administered together they had even greater effects in promoting immunosuppressive Treg cell activities. When administered together prior to an antigen (MOG) that induces experimental autoimmune encephalomyelitis (EAE), IL-2 plus DEX reduced the incidence and severity of EAE in susceptible mice. Thus, upregulation of Tregs by cortisone-derivatives can counteract induction of autoimmune disease. Pertussis toxin (PTX) is coadministered as an adjuvant along with an appropriate autoantigen in Complete Freunds adjuvant (CFA) in order to induce EAE in susceptible mouse strains. This was associated with a decrease in the number of functional Treg cells and concomitant activation of TLR4 by PTX. We established that PTX also has the capacity to induce DC to produce high levels of IL-6. This leads, in conjunction with coproduced TGFbeta, to the activation of the TH17 pathway with copious production of IL-17, which has been implicated in promoting a variety of autoimmune diseases. Thus, we plan to investigate the effect of the rather unique multiplicity of adjuvant effects of PTX on overcoming tolerance to tumor by using it in therapeutic anticancer vaccines. In the current fiscal year my group showed that an immunosuppressive drug, Rapamycin, unlike cyclosporine A, also promotes the generation of functional Tregs, while inhibiting differentiation of Th17 cells. It is therefore a good therapy for autoimmune diseases, but may promote tumor growth. Finally, to our surprise our studies of the effects of various cytokines and alarmins on Tregs revealed that TNF also is a potent upregulator of Treg numbers and activity. Although TNF is a well known proinflammatory cytokine, which has initial activating effects on T efferent cells, later during in vitro and in vivo mouse immune responses especially as a costimulant with IL-2, TNF induces the proliferative expansion of functional Treg cells that preferentially express the TNFR2 receptor. Neither IL-1 nor IL-6 had such biphasic effects. Thus, TNF appears to induce a unique delayed down-regulatory effect on immune responses. This is absent in TNFR2 knockout mice and may account for their less severe (lethal) sepsis (LPS) induced inflammatory reactions. We have further investigated the role of TNFR2 on Tregs and the possibility that tumors by producing TNF may be promoting the increase in Tregs infiltrating tumors with consequent down- regulation of tumor immune responses. We have found that TNFR2+ Tregs (CD4+CD25+FOXP3+) are much more suppressive than TNFR2-Tregs. Tumor infiltrating T cells consist largely of super-suppressive Tregs that inhibit host immune responses to the tumor by T effector cells. A number of lung and breast tumors and their infiltrating leukocytes have been shown to produce TNF. Prel [summary truncated at 7800 characters]