Brown Deborah M, Kamperschroer Cris, Dilzer Allison M, Roberts Deborah M, Swain Susan L
Trudeau Institute, Saranac Lake, NY 12983, USA.
Cell Immunol. 2009;257(1-2):69-79. doi: 10.1016/j.cellimm.2009.03.002. Epub 2009 Mar 31.
CD4 T cell effectors can promote survival against lethal influenza virus via perforin mediated cytolytic mechanisms; however, our understanding of how naïve CD4 cells differentiate into class II restricted killers remains obscure. To address this, TCR Tg CD4 cells were activated in vitro and examined for their ability to lyse target cells. We found that cytokine polarized CD4 T cell effectors displayed cytolytic activity with the hierarchy Th0>Th1>Th2. Further, IL-4 inhibited the generation of cytotoxic CD4 cells. LPS stimulated B cells and bone marrow derived dendritic cells (BMDC) both induced potent cytolytic activity; however, IL-6, TGF-beta, IL-10, IL-12 or TNF-alpha were not required for inducing cytolytic activity in CD4 effectors. Antigen dose had a marked effect on cytotoxicity: low concentrations of peptide induced more potent cytolytic activity than relatively high concentrations. At low peptide concentration, exogenous IL-2 was necessary to drive granzyme B (GrB) expression and perforin mediated lysis. Thus, low antigen dose and early activation signals via IL-2 direct the CD4 T cell response toward effectors with perforin mediated cytolytic potential. These data have implications for the design of vaccines that may induce cytolytic CD4 cells in vivo and improve cell-mediated immunity to viral and bacterial infections.
CD4 T细胞效应器可通过穿孔素介导的细胞溶解机制促进抵抗致死性流感病毒的存活；然而，我们对初始CD4细胞如何分化为II类限制性杀伤细胞的理解仍不清楚。为了解决这个问题，体外激活TCR转基因CD4细胞，并检测其裂解靶细胞的能力。我们发现细胞因子极化的CD4 T细胞效应器表现出细胞溶解活性，其活性顺序为Th0>Th1>Th2。此外，IL-4抑制细胞毒性CD4细胞的产生。LPS刺激的B细胞和骨髓来源的树突状细胞（BMDC）均诱导出强大的细胞溶解活性；然而，诱导CD4效应器的细胞溶解活性并不需要IL-6、TGF-β、IL-10、IL-12或TNF-α。抗原剂量对细胞毒性有显著影响：低浓度肽比相对高浓度诱导出更强的细胞溶解活性。在低肽浓度下，外源性IL-2是驱动颗粒酶B（GrB）表达和穿孔素介导的裂解所必需的。因此，低抗原剂量和通过IL-2的早期激活信号将CD4 T细胞反应导向具有穿孔素介导的细胞溶解潜能的效应器。这些数据对可能在体内诱导细胞毒性CD4细胞并改善对病毒和细菌感染的细胞介导免疫的疫苗设计具有启示意义。
