Messingham Kelly A N, Badovinac Vladimir P, Jabbari Ali, Harty John T
Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
J Immunol. 2007 Aug 15;179(4):2457-66. doi: 10.4049/jimmunol.179.4.2457.
Whether IFN-gamma contributes to the per-cell protective capacity of memory CD8(+) T cells against Listeria monocytogenes (LM) has not been formally tested. In this study, we generated LM Ag-specific memory CD8(+) T cells via immunization of wild-type (WT) and IFN-gamma-deficient (gamma knockout (GKO)) mice with LM peptide-coated dendritic cells and compared them phenotypically and functionally. Immunization of WT and GKO mice resulted in memory CD8(+) T cells that were similar in number, functional avidity, TCR repertoire use, and memory phenotype. The protective capacity of memory CD8(+) T cells from immunized WT and GKO mice was evaluated after adoptive transfer of equal numbers of WT or GKO cells into naive BALB/c mice followed by LM challenge. The adoptively transferred CD8(+) T cells from GKO donors exhibited a decreased ability to reduce bacterial numbers in the organs of recipient mice when compared with an equivalent number of Ag-matched WT CD8(+) T cells. This deficiency was most evident early (day 3) after infection if a relatively low infectious dose was used; however, transferring fewer memory CD8(+) T cells or increasing the LM challenge dose revealed a more pronounced defect in protective immunity mediated by the CD8(+) T cells from GKO mice. Our studies identified a decrease in Ag-specific target cell lysis in vivo by CD8(+) T cells from GKO mice as the mechanism for the decreased protective immunity after LM challenge. Further studies suggest that the lack of IFN-gamma production by the Ag-specific CD8 T cells themselves diminishes target cell sensitivity to cytolysis, thereby reducing the lytic potency of IFN-gamma-deficient LM-specific memory CD8(+) T cells.
γ干扰素是否有助于记忆性CD8(+) T细胞对单核细胞增生李斯特菌（LM）的单细胞保护能力尚未得到正式验证。在本研究中，我们通过用LM肽包被的树突状细胞免疫野生型（WT）和γ干扰素缺陷型（γ敲除（GKO））小鼠，产生了LM抗原特异性记忆性CD8(+) T细胞，并对它们的表型和功能进行了比较。WT和GKO小鼠的免疫产生了数量、功能亲和力、TCR库使用情况和记忆表型相似的记忆性CD8(+) T细胞。在将等量的WT或GKO细胞过继转移到未免疫的BALB/c小鼠中，随后进行LM攻击后，评估了来自免疫的WT和GKO小鼠的记忆性CD8(+) T细胞的保护能力。与等量的抗原匹配的WT CD8(+) T细胞相比，来自GKO供体的过继转移的CD8(+) T细胞在降低受体小鼠器官中细菌数量的能力上有所下降。如果使用相对较低的感染剂量，这种缺陷在感染早期（第3天）最为明显；然而，转移较少数量的记忆性CD8(+) T细胞或增加LM攻击剂量显示，来自GKO小鼠的CD8(+) T细胞介导的保护性免疫存在更明显的缺陷。我们的研究确定，GKO小鼠的CD8(+) T细胞在体内对抗原特异性靶细胞的裂解作用降低是LM攻击后保护性免疫降低的机制。进一步的研究表明，抗原特异性CD8 T细胞自身缺乏γ干扰素产生会降低靶细胞对细胞溶解的敏感性，从而降低γ干扰素缺陷型LM特异性记忆性CD8(+) T细胞的裂解效力。
