Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, Aab Institute for Biomedical Sciences, University of Rochester Medical Center, Rochester, NY 14642-8609, USA.
Immunology. 2011 Apr;132(4):549-58. doi: 10.1111/j.1365-2567.2010.03400.x. Epub 2011 Jan 24.
CD8(+) T-cell responses to non-pathogen, cell-associated antigens such as minor alloantigens or peptide-pulsed dendritic cells (DC) are usually strongly dependent on help from CD4(+) T cells. However, some studies have described help-independent primary CD8(+) T-cell responses to cell-associated antigens, using immunization strategies likely to trigger natural killer (NK) cell activation and inflammatory cytokine production. We asked whether NK cell activation by MHC I-deficient cells, or administration of inflammatory cytokines, could support CD4(+) T-cell help-independent primary responses to peptide-pulsed DC. Injection of MHC I-deficient cells cross-primed CD8(+) T-cell responses to the protein antigen ovalbumin (OVA) and the male antigen HY, but did not stimulate CD8(+) T-cell responses in CD4-depleted mice; hence NK cell stimulation by MHC I-deficient cells did not replace CD4(+) T-cell help in our experiments. Dendritic cells cultured with tumour necrosis factor-α (TNF-α) or type I interferon-α (IFN-α) also failed to prime CD8(+) T-cell responses in the absence of help. Injection of TNF-α increased lymph node cellularity, but did not generate help-independent CD8(+) T-cell responses. In contrast, CD4-depleted mice injected with IFN-α made substantial primary CD8(+) T-cell responses to peptide-pulsed DC. Mice deficient for the type I IFN receptor (IFNR1) made CD8(+) T-cell responses to IFNR1-deficient, peptide-pulsed DC; hence IFN-α does not appear to be a downstream mediator of CD4(+) T-cell help. We suggest that primary CD8(+) T-cell responses will become help-independent whenever endogenous IFN-α secretion is stimulated by tissue damage, infection, or autoimmune disease.
CD8(+) T 细胞对非病原体、细胞相关抗原（如次要同种异体抗原或肽脉冲树突状细胞 (DC)）的反应通常强烈依赖于 CD4(+) T 细胞的帮助。然而，一些研究已经描述了对细胞相关抗原的无需辅助的原发性 CD8(+) T 细胞反应，使用的免疫策略可能触发自然杀伤 (NK) 细胞激活和炎症细胞因子的产生。我们想知道 MHC I 缺陷细胞的 NK 细胞激活或炎症细胞因子的给药是否可以支持对肽脉冲化的 DC 的无需 CD4(+) T 细胞辅助的原发性 CD8(+) T 细胞反应。MHC I 缺陷细胞的注射交叉引发了对蛋白抗原卵清蛋白 (OVA) 和雄性抗原 HY 的 CD8(+) T 细胞反应，但在 CD4 耗尽的小鼠中并未刺激 CD8(+) T 细胞反应；因此，在我们的实验中，MHC I 缺陷细胞的 NK 细胞刺激不能替代 CD4(+) T 细胞的辅助作用。与肿瘤坏死因子-α (TNF-α) 或 I 型干扰素-α (IFN-α) 培养的树突状细胞在没有辅助的情况下也未能引发 CD8(+) T 细胞反应。TNF-α 的注射增加了淋巴结细胞的数量，但未产生无需辅助的 CD8(+) T 细胞反应。相比之下，注射 IFN-α 的 CD4 耗尽的小鼠对肽脉冲化的 DC 产生了大量的原发性 CD8(+) T 细胞反应。缺乏 I 型 IFN 受体 (IFNR1) 的小鼠对缺乏 IFNR1、肽脉冲化的 DC 产生了 CD8(+) T 细胞反应；因此，IFN-α似乎不是 CD4(+) T 细胞辅助的下游介质。我们认为，只要组织损伤、感染或自身免疫性疾病刺激内源性 IFN-α 的分泌，原发性 CD8(+) T 细胞反应就会变得无需辅助。
