Role of T regulatory suppression in autoimmunity and cancer

我们对Tregs的研究表明，TNF通过作用于Tregs高度表达的TNFR2受体，意外地导致Tregs在小鼠和人体内的增殖扩张和功能激活。鉴于TNF众所周知的促炎作用，我们的数据显示TNF以更延迟的方式也可以下调免疫反应，这是相当令人惊讶的。对TNF的这些相互矛盾的作用的一个澄清是基于我们的数据显示，TNF通过激活teeffector细胞也诱导它们表达TNFR2，并对Tregs的抑制作用变得更有抵抗力。因此，炎症部位或自身免疫状态的活化T细胞可以胜过Tregs的抑制作用。然而，随着愈合伤口或非炎症肿瘤的炎症消退，treg占主导地位。大多数肿瘤浸润性T细胞（TIL）实际上表达TNFR2，并被肿瘤源性TNF激活，在外周淋巴组织中比Tregs具有更强的免疫抑制作用。抑制treg应该能够使宿主抗肿瘤反应更有效。因此，我们的初步结果表明，抗tnf可减少小鼠Lewis肺和乳腺（4T1）肿瘤的生长。因此，通过确定对抗Tregs的更好方法，我们可能能够增强对肿瘤疫苗的抗肿瘤反应。

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.