Genetic characterization of strain differences in the ability to mediate CD40/CD28-independent rejection of skin allografts
Genetic characterization of strain differences in the ability to mediate CD40/CD28-independent rejection of skin allografts
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DOI：
10.4049/jimmunol.165.12.6849
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发表时间：
2000-12-15
影响因子：
4.4
通讯作者：
Larsen, CP
中科院分区：
文献类型：
--
作者：
Williams, MA;Trambley, J;Larsen, CP
同时阻断CD40和CD28T细胞共刺激通路有效地促进C3H/HeJ小鼠同种异体皮肤移植的存活，延长中位存活时间(MSTs)超过100天。这一策略在C57BL/6小鼠中的效果明显较差，MST在20天到30天之间。在这项研究中，我们研究了这些不同表型的潜在遗传原因，使用H-2同基因小鼠，我们证明了这两个菌株之间不同反应的遗传基础与H-2基因座和T细胞前体频率无关。共刺激阻断处理的C57BL/6小鼠能够在移植后3-4周内产生同种异体特异性CTL和干扰素-γ产生的T细胞，而C3H背景的小鼠既不产生CTL-也不产生干扰素-γ产生的细胞。因此，不同之处似乎在于免疫反应的产生，而不是T细胞归巢。在缺乏CD4(+)T细胞的情况下，共刺激阻断诱导的低反应性的菌株差异仍然存在，这意味着对CD8(+)T细胞的直接影响。我们证明，在造血细胞中，遗传差异是重要的，并且共刺激拮抗剂抵抗表型占主导地位。对BXH重组自交系的分析表明，BXH重组自交系的表型是由多个基因座决定的，抗性基因座初步与4条染色体上的17个标记连锁。我们得出结论，在CD40/CD28阻断后，同种移植的MSTs的应变变化是由于某些株的CDS的T细胞能够使用不同的共刺激模式来启动有效的同种异体反应。
Simultaneous blockade of the CD40 and CD28 T cell costimulatory pathways effectively promotes skin allograft survival in C3H/HeJ mice, extending median survival times (MSTs) beyond 100 days. This strategy is markedly less effective in C57BL/6 mice, with MSTs ranging between 20 and 30 days. In this study, we investigate the underlying genetic causes of these distinct phenotypes, Using H-2 congenic mice, we show that the genetic basis for the varied responses between these two strains is independent of the H-2 locus and T cell precursor frequency. C57BL/6 mice treated with costimulation blockade are able to generate allospecific CTL- and IFN-gamma -producing T cells within 3-4 wk posttransplant, whereas mice with a C3H background generate neither CTL- nor IFN-gamma -producing cells. Thus, differences appear to be in the generation of the immune response and not T cell homing. Strain differences in costimulation blockade-induced hyporesponsiveness persist in the absence of CD4(+) T cells, implying a direct effect on CD8(+) T cells. We demonstrate that genetic differences are important in cells of hemopoietic origin and that the costimulation blockade-resistant phenotype is dominant. Analysis of BXH recombinant inbred strains indicates that multiple loci contribute to the phenotype, and that the blockade resistance loci are preliminarily linked to 17 markers on four chromosomes. We conclude that strain variation in allograft MSTs following CD40/CD28 blockade results from the ability of CDS' T cells in some strains to use alternative modes of costimulation to mount an effective alloresponse.