Role of T regulatory suppression in autoimmunity and cancer

最近已经清楚的是，T细胞的子集例如T调节（Treg）细胞对免疫应答具有反馈抑制作用。据报道，这些Treg细胞抑制自身免疫反应，因此不幸的是，也被报道保护肿瘤免受免疫排斥。我们先前表明，用于治疗自身免疫性疾病的免疫抑制剂地塞米松（DEX）和淋巴增殖细胞因子白细胞介素-2各自上调小鼠Treg细胞的数量和功能。此外，当一起施用时，它们在促进免疫抑制性Treg细胞活性方面具有更大的作用。当在诱导实验性自身免疫性脑脊髓炎（EAE）的抗原（MOG）之前一起施用时，IL-2加DEX降低易感小鼠中EAE的发生率和严重程度。因此，通过可的松衍生物上调TcB可以抵消自身免疫反应的诱导。百日咳毒素（PTX）作为佐剂与完全弗氏佐剂（CFA）中的适当自身抗原一起沿着施用，以在易感小鼠品系中诱导EAE。这与功能性Treg细胞数量的减少以及PTx对TLR 4的伴随激活有关。在本财政年度期间，我们确定PTx也具有诱导DC产生高水平IL-6的能力。这与共同产生的TGF β一起导致TH 17途径的激活，并大量产生IL-17，这与促进多种自身免疫性疾病有关。因此，我们计划通过将PTx用于治疗性抗癌疫苗来研究PTx的相当独特的多重佐剂效应对克服肿瘤耐受性的影响。最后，令我们惊讶的是，我们对各种细胞因子和警报素对Treg影响的研究表明，TNF也是Treg数量和活性的有效上调剂。虽然TNF是一种众所周知的促炎细胞因子，其对T传出细胞具有初始激活作用，但随后在体外和体内小鼠免疫应答中，特别是作为与IL-2的共刺激剂，TNF诱导表达TNFR 2受体的功能性Treg细胞的增殖性扩增。IL-1和IL-6都没有这种双相效应。因此，TNF似乎诱导对免疫应答的独特的延迟下调调节作用。这在TNFR 2敲除小鼠中是不存在的，并且可以解释它们更严重（致死）的脓毒性（LPS）诱导的炎症反应。我们正在进一步研究TNFR 2对TcB的作用，以及肿瘤通过产生TNF可能促进肿瘤中检测到的浸润性TcB增加，从而下调肿瘤免疫应答的可能性。

It has recently become clear that a subset of T cells e.g. T regulatory (Treg) cells have feedback suppressive effects on immune responses. These Treg cells have been reported to suppress autoimmune responses and consequently, unfortunately, also are reported to protect tumors from immune rejection. 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 and function 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 reactions. 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. During the current fiscal year 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. 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 in 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 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 more severe (lethal) septic (LPS) induced inflammatory reactions. We are further investigating the role of TNFR2 on Tregs and the possibility that tumors by producing TNF may be promoting the increase in infiltrating Tregs detected in tumors with consequent down regulation of tumor immune responses.