CD4⁺ T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses^1,2,3,4,5, other CD4⁺ T cells have recently been implicated in inhibiting this response^6,7. Yet, the nature and function of the latter remain unclear. Here, using vaccines containing MHC class I (MHC-I) neoantigens (neoAgs) and different doses of tumour-derived MHC-II neoAgs, we discovered that whereas the inclusion of vaccines with low doses of MHC-II-restricted peptides (LDVax) promoted tumour rejection, vaccines containing high doses of the same MHC-II neoAgs (HDVax) inhibited rejection. Characterization of the inhibitory cells induced by HDVax identified them as type 1 regulatory T (Tr1) cells expressing IL-10, granzyme B, perforin, CCL5 and LILRB4. Tumour-specific Tr1 cells suppressed tumour rejection induced by anti-PD1, LDVax or adoptively transferred tumour-specific effector T cells. Mechanistically, HDVax-induced Tr1 cells selectively killed MHC-II tumour antigen-presenting type 1 conventional dendritic cells (cDC1s), leading to low numbers of cDC1s in tumours. We then documented modalities to overcome this inhibition, specifically via anti-LILRB4 blockade, using a CD8-directed IL-2 mutein, or targeted loss of cDC2/monocytes. Collectively, these data show that cytotoxic Tr1 cells, which maintain peripheral tolerance, also inhibit antitumour responses and thereby function to impede immune control of cancer.

CD4 ⁺ T细胞可以增强或抑制肿瘤免疫。尽管人们早就知道调节性 T 细胞会阻碍抗肿瘤反应^1,2,3,4,5 ，但其他 CD4 ⁺ T 细胞最近也被认为参与了抑制这种反应^6,7 。然而，后者的性质和功能仍不清楚。在这里，使用含有 MHC I 类 (MHC-I) 新抗原 (neoAgs) 和不同剂量的肿瘤来源的 MHC-II neoAgs 的疫苗，我们发现，而包含低剂量 MHC-II 限制性肽 (LDVax) 的疫苗促进肿瘤排斥，而含有高剂量相同 MHC-II neoAg (HDVax) 的疫苗则抑制排斥。 HDVax 诱导的抑制细胞的特征鉴定为表达 IL-10、颗粒酶 B、穿孔素、CCL5 和 LILRB4 的 1 型调节性 T (Tr1) 细胞。肿瘤特异性 Tr1 细胞可抑制抗 PD1、LDVax 或过继转移的肿瘤特异性效应 T 细胞诱导的肿瘤排斥。从机制上讲，HDVax 诱导的 Tr1 细胞选择性杀死 MHC-II 肿瘤抗原呈递 1 型常规树突状细胞 (cDC1)，导致肿瘤中 cDC1 数量减少。然后，我们记录了克服这种抑制的方法，特别是通过抗 LILRB4 阻断、使用 CD8 定向的 IL-2 突变蛋白或靶向损失 cDC2/单核细胞。总的来说，这些数据表明，维持外周耐受性的细胞毒性 Tr1 细胞也能抑制抗肿瘤反应，从而阻碍癌症的免疫控制。