Tomita Y, Mayumi H, Eto M, Nomoto K
Department of Immunology, Kyushu University, Fukuoka, Japan.
J Immunol. 1990 Mar 15;144(6):2425-35.
Presence of the three major pathways (self-Ia restricted, allo-K/D restricted, and allo-Ia restricted pathways) in generating class I-restricted CTL has been reported. The present study was conducted in order to clarify which of the three is the main pathway in mediating tumor allograft rejection. One million EL-4 tumor cells derived from C57BL/6 (B6;H-2b) were inoculated into the various strains of mice that were genetically different from B6. Class I (K/D) Ag-disparate but IA Ag-matched B6.C-H-2bm1 (bm1;Kbm1, IAb, IE-, Db) mice or B10.A (5R) (5R; b, b, k, d) mice could not reject 1 x 10(6) EL-4 tumor cells in spite of the strong generation of CTL against the B6 Ag, suggesting the inability of the self-Ia restricted pathway and the allo-K/D restricted pathway in rejecting tumor allografts. The strains of mice being capable of rejecting EL-4 tumor were disparate from B6 mice in both class I and class II (IA) Ag, suggesting the importance of the allo-Ia restricted pathway in rejecting tumor allografts. To generate CTL against Kb Ag via the allo-Ia restricted pathway in the bm1 mice, 2 x 10(7) B6.H-2bm12 (bm12; b, bm12, -, b) spleen cells were injected into the bm1 mice as a supplementary source of allogeneic APC that possibly raise CTL through CD4+ Th cells of bm1 origin. These bm1 mice became capable of rejecting 1 x 10(6) EL-4 tumor cells. The same was observed in the combination of bm12----B10.A (5R) (b, b, k, d) mice. To further elucidate the role of the class II restricted CD4+ Th cells, anti-CD4 antibody was repeatedly i.v. administered into the C3H/He (C3H; H-2k) or the DBA/2 (DBA; H-2d) mice on days 0, 1, and 4. Injection of anti-CD4 antibody led 1 x 10(6) EL-4 tumor cells to grow and kill the C3H and DBA mice. These results suggest that the main effector CTL pathway involved in tumor allograft rejection is allo-Ia restricted pathway where CD8+ precursor CTL were stimulated by the class II-restricted CD4+ Th cells.
据报道，在产生I类限制性细胞毒性T淋巴细胞（CTL）过程中存在三种主要途径（自身Ia限制性途径、同种异体K/D限制性途径和同种异体Ia限制性途径）。本研究旨在阐明这三种途径中哪一种是介导肿瘤同种异体移植排斥反应的主要途径。将源自C57BL/6（B6；H-2b）的100万个EL-4肿瘤细胞接种到与B6基因不同的各种小鼠品系中。I类（K/D）抗原不同但Ia抗原匹配的B6.C-H-2bm1（bm1；Kbm1，IAb，IE-，Db）小鼠或B10.A（5R）（5R；b，b，k，d）小鼠尽管能强烈产生针对B6抗原的CTL，但仍无法排斥1×10⁶个EL-4肿瘤细胞，这表明自身Ia限制性途径和同种异体K/D限制性途径无法排斥肿瘤同种异体移植。能够排斥EL-4肿瘤的小鼠品系在I类和II类（Ia）抗原上均与B6小鼠不同，这表明同种异体Ia限制性途径在排斥肿瘤同种异体移植中具有重要性。为了通过bm1小鼠中的同种异体Ia限制性途径产生针对Kb抗原的CTL，将2×10⁷个B6.H-2bm12（bm12；b，bm12，-，b）脾细胞作为同种异体抗原呈递细胞（APC）的补充来源注射到bm1小鼠体内，这些APC可能通过bm1来源的CD4⁺辅助性T细胞（Th细胞）激活CTL。这些bm1小鼠变得能够排斥1×10⁶个EL-4肿瘤细胞。在bm12与B10.A（5R）（b，b，k，d）小鼠的组合中也观察到了同样的情况。为了进一步阐明II类限制性CD4⁺ Th细胞的作用，在第0、1和4天通过静脉反复给C3H/He（C3H；H-2k）或DBA/2（DBA；H-2d）小鼠注射抗CD4抗体。注射抗CD4抗体导致1×10⁶个EL-4肿瘤细胞生长并杀死C3H和DBA小鼠。这些结果表明，参与肿瘤同种异体移植排斥反应的主要效应CTL途径是同种异体Ia限制性途径，其中CD8⁺前体CTL受到II类限制性CD4⁺ Th细胞的刺激。
