Role of T Regulatory Cell Suppression in Autoimmunity and Cancer

我们对Tregs的研究表明，TNF通过作用于Tregs最高度表达的TNFR2受体，意外地导致Tregs在小鼠和人体内的增殖扩增和功能激活。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。此外，TNF与IL-2一起上调TNFR2以及4-1BB和OX-40受体的细胞表面表达。因此，TNF通过诱导3个TNFRSF成员来放大其对treg的刺激作用。TNF与TNFR2的相互作用也稳定了炎症部位的CD4+FOXP3+ T调节细胞表型。对TNF的这些意想不到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更多的TNFR2，并对Tregs的抑制作用变得更有抵抗力。因此，激活的炎症部位可以战胜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，Tregs占上风。约50%的肿瘤浸润性T细胞（TIL）发展为Tregs并表达TNFR2。它们被肿瘤衍生的TNF激活，比外周淋巴组织中的treg具有更强的免疫抑制作用。抑制Tregs导致更有效的宿主抗肿瘤反应和抑制肿瘤生长。我们假设TNFR2可以作为Tregs的“检查点抑制剂”发挥作用。我们通过中和抗tnfalpha（抑制Tregs和CpG，一种TLR9配体，从而促进细胞介导的免疫）治疗携带4T1乳腺肿瘤的小鼠，验证了这一假设。这导致80%的小鼠无肿瘤，并优先抵抗随后的4T1肿瘤攻击。这些经处理的小鼠肿瘤中产生IFNgamma的细胞大量浸润，而不是Treg TIL细胞，并且脾脏和肿瘤中MDSC的数量也减少。这些发现表明，这种疗法使小鼠表现出相当大的抗肿瘤免疫力。鉴定出更有效的TNFR2拮抗剂应该会产生更有效的检查点抑制。

Our studies of Tregs have revealed that TNF by acting on the TNFR2 receptor, which is most highly expressed by Tregs, unexpectedly results in the proliferative expansion and functional activation of Tregs 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. Furthermore, TNF together with IL-2 up-regulates the cell surface expression of TNFR2 and also of 4-1BB and OX-40 receptors. Thus, TNF amplifies its stimulatory effect on Tregs by inducing 3 TNFRSF members. TNF interactions with TNFR2 also stabilizes the CD4+FOXP3+ T regulatory cell phenotype at inflammatory sites. One clarification of these unexpected effects of TNF is based on our data showing that TNF by activating Teffector cells also induce them to express more TNFR2 and to become more resistant to the suppressive effects of Tregs. Thus activated inflammatory sites can prevail over the suppressive effects of Tregs. However, as inflammation subsides in healing wounds or in non-inflamed tumors, Tregs prevail. About 50% tumor infiltrating T cells (TIL's) develop into Tregs and express TNFR2. They are activated by tumor-derived TNF to be even more immunosuppressive than Tregs in peripheral lymphoid tissues. Suppression of Tregs results in more effective host antitumor responses and suppresses tumor growth. We hypothesize that TNFR2 can function as a "checkpoint inhibitor" of Tregs. This hypothesis was tested by us by treating mice bearing 4T1 mammary tumors with neutralizing anti-TNFalpha, which suppresses Tregs, and CpG, a TLR9 ligand thus promoting cell mediated immunity. This resulted in 80% of the mice becoming tumor free and preferentially resisting a subsequent 4T1 tumor challenge. These treated mice developed considerable infiltration of their tumors by IFNgamma producing rather than Treg TIL cells and also reduced the numbers of MDSC in their spleens and tumors. These finding suggest that this therapy enabled the mice to exhibit considerable antitumor immunity. Identification of more potent antagonists of TNFR2 should yield even more effective checkpoint inhibition.