Richards D M, Zhang N, Dalheimer S L, Mueller D L
Department of Medicine, and Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA.
Am J Transplant. 2007 Oct;7(10):2269-78. doi: 10.1111/j.1600-6143.2007.01934.x.
To investigate the mechanism of CD4(+) T-cell help during the activation and differentiation of directly alloreactive CD8(+) T cells, we examined the development of obliterative airways disease (OAD) following transplantation of airways into fully mismatched recipient mice deficient in CD4(+) T cells. BALB/c trachea allografts became fibrosed significantly less frequently in B6 CD4(-/-) recipients as compared to wildtype controls. Furthermore, class I-directed cytotoxicity failed to develop in the absence of CD4(+) T cells. The infiltration of graft tissue by primed L(d)-specific directly alloreactive 2C CD8(+) T cells was not found to depend on the presence of CD4(+) T cells. Nevertheless, graft-infiltrating 2C CD8(+) T cells failed to express CD69 and granzyme B when CD4(+) T-cell help was unavailable. Importantly, reconstitution of B6 CD4(-/-) recipient mice with graft peptide-specific TCR-Tg CD4(+) T cells (OT-II or TEa) capable of recognizing antigen only on recipient APC allowed for full expression of CD69 and granzyme B by the directly alloreactive CD8(+) T cells and restored the capacity of recipients to reject their allografts. These results demonstrate that indirectly alloreactive CD4(+) T cells ensure the optimal activation and differentiation of graft-infiltrating directly alloreactive CD8(+) T cells independent of donor APC recognition.
为了研究直接同种异体反应性CD8⁺ T细胞活化和分化过程中CD4⁺ T细胞辅助的机制，我们检测了将气道移植到完全不匹配的CD4⁺ T细胞缺陷受体小鼠后闭塞性气道疾病（OAD）的发展情况。与野生型对照相比，B6 CD4⁻/⁻受体中BALB/c气管同种异体移植物纤维化的频率显著降低。此外，在没有CD4⁺ T细胞的情况下，I类定向细胞毒性未能发展。已致敏的L(d)特异性直接同种异体反应性2C CD8⁺ T细胞对移植组织的浸润并不依赖于CD4⁺ T细胞的存在。然而，当没有CD4⁺ T细胞辅助时，移植浸润的2C CD8⁺ T细胞无法表达CD69和颗粒酶B。重要的是，用仅能识别受体APC上抗原的移植肽特异性TCR-Tg CD4⁺ T细胞（OT-II或TEa）重建B6 CD4⁻/⁻受体小鼠，可使直接同种异体反应性CD8⁺ T细胞充分表达CD69和颗粒酶B，并恢复受体排斥其同种异体移植物的能力。这些结果表明，间接同种异体反应性CD4⁺ T细胞可确保移植浸润的直接同种异体反应性CD8⁺ T细胞的最佳活化和分化，而与供体APC识别无关。
