Rosenberg A S, Mizuochi T, Singer A
Immunology Branch, National Cancer Institute, Bethesda, Maryland 20892.
J Exp Med. 1988 Jul 1;168(1):33-45. doi: 10.1084/jem.168.1.33.
The present study further characterizes the cellular mechanisms involved in the in vivo rejection of MHC class I-disparate skin allografts. Previously, we demonstrated that class I-specific rejection responses could result from collaborations between distinct populations of lymphokine-secreting T helper (Th) and lymphokine-responsive T effector (Teff) cells. In the present study, we have assessed the possibility that class I-specific rejection responses could also result from a second cellular mechanism involving a single population of dual-function Th/Teff cells that would not have any further requirement for cell-cell collaboration. Our experimental strategy was to determine the ability of MHC class I-allospecific T cells, in response to class I allodeterminants expressed on skin grafts, to provide help in vivo for activation of helper-dependent Teff cells. We found that class I anti-Kbm1-allospecific T cells would reject bm1 skin allografts, but would not generate help for the activation of helper-dependent effector cells that were specific for third-party skin allografts (e.g., grafts expressing Kbm6, Qa1a, or H-Y allodeterminants). This failure of anti-Kbm1 T cells to provide help in response to bm1 skin allografts was not due to an inability of lymphokine-secreting anti-Kbm1 Th cells to recognize and respond in vivo to Kbm1 allodeterminants expressed on skin, since lymphokine-secreting anti-Kbm1 Th cells were specifically primed in animals engrafted with bm1 skin allografts. Nor was any evidence found that this failure was due to active suppression of anti-Kbm1 helper activity. Rather, we found that anti-Kbm1 T cells consumed nearly all of the helper factors they secreted. Taken together, these results are most consistent with the in vivo activity of dual-function Th/Teff cells that consume the lymphokines they secrete. Thus, this study demonstrates that MHC class I-disparate skin allografts can be rejected by two mechanisms, depending on the ability of the allospecific Teff cell to secrete helper lymphokines. MHC class I-disparate grafts can be rejected by (a) class I-allospecific Teff cells that are unable to produce lymphokine but are responsive to exogenous T cell help; and (b) class I-allospecific dual-function Th/Teff cells that are able to both produce and consume soluble lymphokine.
本研究进一步阐述了体内MHC I类不相合皮肤同种异体移植排斥反应所涉及的细胞机制。此前，我们证明I类特异性排斥反应可能源于分泌淋巴因子的辅助性T（Th）细胞和对淋巴因子有反应的效应性T（Teff）细胞的不同群体之间的协作。在本研究中，我们评估了I类特异性排斥反应也可能源于第二种细胞机制的可能性，该机制涉及单一群体的双功能Th/Teff细胞，不再需要细胞间协作。我们的实验策略是确定MHC I类同种异体特异性T细胞在对皮肤移植物上表达的I类同种异体决定簇作出反应时，在体内为辅助依赖性Teff细胞的激活提供帮助的能力。我们发现，I类抗Kbm1同种异体特异性T细胞会排斥bm1皮肤同种异体移植物，但不会为针对第三方皮肤同种异体移植物（例如表达Kbm6、Qa1a或H-Y同种异体决定簇的移植物）的辅助依赖性效应细胞的激活提供帮助。抗Kbm1 T细胞在对bm1皮肤同种异体移植物作出反应时无法提供帮助，这并非由于分泌淋巴因子的抗Kbm1 Th细胞无法在体内识别并对皮肤表达的Kbm1同种异体决定簇作出反应，因为分泌淋巴因子的抗Kbm1 Th细胞在植入bm1皮肤同种异体移植物的动物中被特异性致敏。也没有发现任何证据表明这种失败是由于抗Kbm1辅助活性的主动抑制。相反，我们发现抗Kbm1 T细胞消耗了它们分泌的几乎所有辅助因子。综上所述，这些结果与消耗自身分泌的淋巴因子的双功能Th/Teff细胞的体内活性最为一致。因此，本研究表明，MHC I类不相合的皮肤同种异体移植物可通过两种机制被排斥，这取决于同种异体特异性Teff细胞分泌辅助性淋巴因子的能力。MHC I类不相合的移植物可被以下两种方式排斥：（a）不能产生淋巴因子但对外源性T细胞帮助有反应的I类同种异体特异性Teff细胞；（b）既能产生又能消耗可溶性淋巴因子的I类同种异体特异性双功能Th/Teff细胞。
