Li T, Harada M, Tamada K, Abe K, Nomoto K
Department of Immunology, Kyushu University, Fukuoka, Japan.
Anticancer Res. 1997 Nov-Dec;17(6D):4259-68.
Stressful events suppress a broad spectrum of immunological responses. However, the effects of stress on the antitumor T cell response against syngeneic tumors have not yet been closely studied. In the present study, we investigated the effects of repeated restraint stress on the antitumor T cell response against syngeneic B16 melanoma. The stress, before and after immunization with tumor cells, decreased the potential of the spleen cells to turn into antitumor cytotoxic T lymphocytes (CTLs) after in vitro restimulation. In a cytokine assay, the stress significantly suppressed the tumor-specific CD4+ T cell-dependent IFN-gamma production of immunized spleen cells. The stress also decreased their spontaneous IL-2 production, but it apparently had no effect on IL-4 production. The in vitro addition of IL-2, however, restored the stress-induced inability of the spleen cells to turn into antitumor CTLs after in vitro restimulation, thus suggesting that stress has no definite effect on tumor-specific CD8+ T cells. Stress had no effect on the natural killer (NK) activity of the spleen cells, but did decrease their responsiveness to poly (I:C), an NK activity augmentator. In addition, stress did not influence primary tumor growth but did decrease the degree of protective immunity at rechallenge. On the other hand, stress elevated the serum level of corticosterone and, in addition, the in vivo administration of dexamethasone, a synthetic glucocorticoid, decreased the capacity of the immunized spleen cells to turn into antitumor CTLs after in vitro restimulation and to produce both IFN-gamma and IL-2 in a manner similar to that of mice burdened by stress. Moreover, stress decreased the potential of spleen cells to produce both IFN-gamma and IL-2 in response to anti-CD3 mAb. Overall, these findings provide evidence that stress significantly impairs the antitumor T cell responses through its suppressive effect on Th1-type CD4+ T cells.
应激事件会抑制广泛的免疫反应。然而，应激对同基因肿瘤的抗肿瘤T细胞反应的影响尚未得到深入研究。在本研究中，我们调查了重复束缚应激对同基因B16黑色素瘤的抗肿瘤T细胞反应的影响。在肿瘤细胞免疫前后施加应激，会降低体外再刺激后脾细胞转化为抗肿瘤细胞毒性T淋巴细胞（CTLs）的潜能。在细胞因子检测中，应激显著抑制了免疫脾细胞中肿瘤特异性CD4+ T细胞依赖的IFN-γ产生。应激还降低了它们的自发IL-2产生，但对IL-4产生显然没有影响。然而，体外添加IL-2可恢复应激诱导的脾细胞在体外再刺激后无法转化为抗肿瘤CTLs的能力，因此表明应激对肿瘤特异性CD8+ T细胞没有明确影响。应激对脾细胞的自然杀伤（NK）活性没有影响，但确实降低了它们对聚肌胞苷酸（poly (I:C)）（一种NK活性增强剂）的反应性。此外，应激不影响原发性肿瘤生长，但会降低再次攻击时的保护性免疫程度。另一方面，应激会升高血清皮质酮水平，此外，体内给予地塞米松（一种合成糖皮质激素）会降低免疫脾细胞在体外再刺激后转化为抗肿瘤CTLs的能力，并以类似于受应激小鼠的方式降低IFN-γ和IL-2的产生。此外，应激降低了脾细胞对抗CD3单克隆抗体产生IFN-γ和IL-2的潜能。总体而言，这些发现提供了证据，表明应激通过对Th1型CD4+ T细胞的抑制作用显著损害抗肿瘤T细胞反应。
