Nomura Masaru, Hodgkinson Suzanne J, Tran Giang T, Verma Nirupama D, Robinson Catherine, Plain Karren M, Boyd Rochelle, Hall Bruce M
Immune Tolerance Group, Faculty of Medicine, UNSW Australia, Sydney and Ingham Institute Liverpool Hospital, NSW, Australia.
Immune Tolerance Group, Faculty of Medicine, UNSW Australia, Sydney and Ingham Institute Liverpool Hospital, NSW, Australia.
Transpl Immunol. 2017 Jun;42:24-33. doi: 10.1016/j.trim.2017.05.002. Epub 2017 May 6.
CD4T cells that transfer alloantigen-specific transplant tolerance are short lived in culture unless stimulated with specific-donor alloantigen and lymphocyte derived cytokines. Here, we examined if IFN-γ maintained survival of tolerance transferring CD4T cells. Alloantigen-specific transplant tolerance was induced in DA rats with heterotopic adult PVG heart allografts by a short course of immunosuppression and these grafts functioned for >100days with no further immunosuppression. In previous studies, we found the CD4T cells from tolerant rats that transfer tolerance to an irradiated DA host grafted with a PVG heart, lose their tolerance transferring ability after 3days of culture, either with or without donor alloantigen, and effect rejection of specific-donor grafts. If cultures with specific-donor alloantigen are supplemented by supernatant from ConA activated lymphocytes the tolerance transferring cells survive, suggesting these cells depend on cytokines for their survival. In this study, we found addition of rIFN-γ to MLC with specific-donor alloantigen maintained the capacity of tolerant CD4T cells to transfer alloantigen-specific tolerance and their ability to suppress PVG allograft rejection mediated by co-administered naïve CD4T cells. IFN-γ suppressed the in vitro proliferation of tolerant CD4T cells. Tolerant CD4CD25T cells did not proliferate in MLC to PVG stimulator cells with no cytokine added, but did when IFN-γ was present. IFN-γ did not alter proliferation of tolerant CD4CD25T cells to third-party Lewis. Tolerant CD4CD25T cells' expression of IFN-γ receptor (IFNGR) was maintained in culture when IFN-γ was present. This study suggested that IFN-γ maintained tolerance mediating alloantigen-specific CD4CD25T cells.
除非用特定供体的同种异体抗原和淋巴细胞衍生的细胞因子进行刺激，否则传递同种异体抗原特异性移植耐受的CD4 T细胞在培养中寿命短暂。在此，我们研究了IFN-γ是否能维持传递耐受的CD4 T细胞的存活。通过短期免疫抑制在DA大鼠中诱导了异位成年PVG心脏同种异体移植的同种异体抗原特异性移植耐受，这些移植物在没有进一步免疫抑制的情况下功能超过100天。在先前的研究中，我们发现来自耐受大鼠的CD4 T细胞，将耐受传递给移植了PVG心脏的受照射DA宿主，在培养3天后，无论有无供体同种异体抗原，都会失去其耐受传递能力，并导致特定供体移植物的排斥。如果用ConA激活的淋巴细胞的上清液补充含有特定供体同种异体抗原的培养物，耐受传递细胞就能存活，这表明这些细胞的存活依赖于细胞因子。在本研究中，我们发现在含有特定供体同种异体抗原的混合淋巴细胞培养中添加rIFN-γ，可维持耐受CD4 T细胞传递同种异体抗原特异性耐受的能力，以及它们抑制由共同给予的未致敏CD4 T细胞介导的PVG同种异体移植排斥的能力。IFN-γ抑制了耐受CD4 T细胞的体外增殖。在不添加细胞因子的情况下，耐受的CD4CD25 T细胞在与PVG刺激细胞的混合淋巴细胞培养中不增殖，但在有IFN-γ存在时会增殖。IFN-γ不会改变耐受的CD4CD25 T细胞对第三方Lewis细胞的增殖。当存在IFN-γ时，耐受的CD4CD25 T细胞在培养中维持IFN-γ受体（IFNGR）的表达。本研究表明，IFN-γ维持了介导同种异体抗原特异性的CD4CD25 T细胞的耐受。
