Role of T regulatory suppression in autoimmunity and cancer

T 调节抑制在自身免疫和癌症中的作用

• 批准号: 8157403
• 负责人: JOOST J OPPENHEIM
• 金额: $ 46.76万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8157403
• 关键词: Autoimmunity; Malignant Neoplasms; Role

Our studies of Tregs have revealed that TNF by acting on the TNFR2 receptor, which is highly expressed by Tregs, unexpectedly results in their proliferative expansion and functional activation both in mice and in man. In view of the well known proinflammatory effects of TNF, our data showing that TNF in a more delayed manner can also down-regulate immune responses is rather surprising. One clarification of these contradictory effects of TNF is based on our data showing that TNF by activating Teffector cells also induces them to express TNFR2 and to become more resistant to the suppressive effects of Tregs. Thus, activated T cells at inflammatory sites or in autoimmune status can prevail over the suppressive effects of Tregs. However, as inflammation subsides in healing wounds or in noninflamed tumors Tregs prevail. Most tumor infiltrating T cells (TIL's) actually express TNFR2 and are activated by tumor-derived TNF to be even more immunosuppressive than Tregs in peripheral lymphoid tissues. Suppression of Tregs should enable more effect host anti-tumor responses to become evident. Consequently, our preliminary results show that anti-TNF reduced the growth of mouse Lewis lung and breast (4T1) tumors. Thus, by identifying better means of countering Tregs, we may be able to enhance antitumor responses to tumor vaccines.

我们对Tregs的研究表明，通过在TNFR2受体上作用TNF，TNF由Tregs高度表达，意外地导致了它们在小鼠和人类中的增殖膨胀和功能激活。鉴于TNF的众所周知的促炎作用，我们的数据表明，以更延迟的方式TNF也可以下调免疫反应是令人惊讶的。对TNF的这些矛盾效应的一个澄清是基于我们的数据表明，TNF通过激活Teffector细胞也诱导它们表达TNFR2，并对Tregs的抑制作用具有更大的抵抗力。因此，在炎症部位或自身免疫性状态处的活化的T细胞可以在Treg的抑制作用中占上风。然而，随着炎症消退，愈合伤口或非炎性肿瘤tregs占了上风​​。大多数肿瘤浸润的T细胞（TIL）实际上表达了TNFR2，并被肿瘤衍生的TNF激活，比外周淋巴组织中的Tregs更为免疫抑制。 Tregs的抑制应使更多效应宿主的抗肿瘤反应变得明显。因此，我们的初步结果表明，抗TNF减少了小鼠刘易斯肺和乳腺（4T1）肿瘤的生长。因此，通过确定更好的Treg手段，我们可能能够增强对肿瘤疫苗的抗肿瘤反应。