Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation
Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation
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DOI：
10.4049/jimmunol.165.2.779
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发表时间：
2000-07-15
影响因子：
4.4
通讯作者：
Chen, SB
中科院分区：
文献类型：
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作者：
Kusmartsev, SA;Li, Y;Chen, SB
T细胞的激活是发展特异性抗肿瘤免疫反应的必要步骤，在本研究中，我们评估了来自肿瘤小鼠骨髓或脾脏的Gr-1（+）髓样细胞抑制CD3/ cd28介导的T细胞激活的能力。利用流式细胞术，我们发现小鼠结肠癌（MCA-26）的生长诱导肿瘤宿主骨髓和脾脏中Gr-1（+）和Gr-1(+)/Mac-1（+）髓样细胞的数量显著增加。当用抗cd3和抗cd28抗体激活初始T细胞时，来自荷瘤小鼠的脾脏或骨髓的骨髓富集细胞部分与来自初始小鼠的骨髓的细胞部分存在，T细胞的增殖反应显著降低。通过分别添加mntpap（锰[III]四基[4-苯甲酸]）卟啉和L-NMMA （n - g -单甲基- l-精氨酸）（一种模拟超氧化物歧化酶和诱导型NO合成酶抑制剂）的组合，或通过消耗gr -1阳性细胞，可以逆转抑制作用。ifn - γ是由CD3/ cd28刺激的幼稚T细胞内源性产生的，参与骨髓细胞抑制活性的诱导。重要的是，当使用抗CD3抗体预先激活的T细胞作为应答细胞时，骨髓或脾脏来源的Gr-1（+）骨髓细胞无法抑制CD3/ cd28诱导的T细胞增殖。我们的研究结果表明，增加免疫抑制性Gr-1（+）细胞数量诱导肿瘤宿主T细胞无反应性或免疫耐受的一种机制可能是在原代T细胞激活时产生过氧亚硝酸盐。
Activation of T cells is a necessary step in the development of a specific antitumor immune response, In the present study, we evaluated the ability of Gr-1(+) myeloid cells, derived from the bone marrow or spleen of tumor-bearing mice, to inhibit CD3/CD28-mediated T cell activation. Using flow cytometry, we found that growth of a murine colon carcinoma (MCA-26) induces a significant increase in the number of Gr-1(+) and Gr-1(+)/Mac-1(+) myeloid cells in both bone marrow and spleen of the tumor host. The proliferative response of T cells was dramatically decreased when naive T cells were activated by anti-CD3 and anti-CD28 Abs in the presence of a myeloid-enriched cell fraction derived from spleen or bone marrow of tumor-bearing mice vs the bone marrow of naive mice. Reversal of the inhibitory effect could be achieved by adding a combination of MnTBAP (manganese [III] tetrakis [4-benzoic acid]) porphyrin and L-NMMA (N-G-monomethyl-L-arginine), a superoxide dismutase mimetic and inducible NO synthase inhibitor, respectively, or by depletion of the Gr-1-positive cells. IFN-gamma, which is endogenously produced by CD3/CD28-stimulated naive T cells, is involved in induction of the inhibitory activity of myeloid cells. Importantly, when T cells pre-activated with anti-CD3 Abs were used as responder cells, the bone marrow- or spleen-derived Gr-1(+) myeloid cells were unable to suppress CD3/CD28-induced T cell proliferation. Our findings suggest that one mechanism by which an increased number of immune suppressive Gr-1(+) cells can induce T cell unresponsiveness or immune tolerance in tumor hosts could be through peroxynitrite production upon primary T cell activation.