Sarikonda Ghanashyam, Wang Hong, Puan Kia-Joo, Liu Xiao-hui, Lee Hoi K, Song Yongcheng, Distefano Mark D, Oldfield Eric, Prestwich Glenn D, Morita Craig T
Department of Internal Medicine, Division of Rheumatology, niversity of Iowa College of Medicine, Iowa City, IA 52242, USA.
J Immunol. 2008 Dec 1;181(11):7738-50. doi: 10.4049/jimmunol.181.11.7738.
Vgamma2Vdelta2 T cells comprise the major subset of peripheral blood gammadelta T cells in humans and expand during infections by recognizing small nonpeptide prenyl pyrophosphates. These molecules include (E)-4-hydroxy-3-methyl-but-2-enyl-pyrophosphate (HMBPP), a microbial isoprenoid intermediate, and isopentenyl pyrophosphate, an endogenous isoprenoid intermediate. Recognition of these nonpeptide Ags is mediated by the Vgamma2Vdelta2 T cell Ag receptor. Several findings suggest that prenyl pyrophosphates are presented by an Ag-presenting molecule: contact between T cells and APC is required, the Ags do not bind the Vgamma2Vdelta2 TCR directly, and Ag recognition is abrogated by TCR mutations in CDRs distant from the putative Ag recognition site. Identification of the putative Ag-presenting molecule, however, has been hindered by the inability to achieve stable association of nonpeptide prenyl pyrophosphate Ags with the presenting molecule. In this study, we show that photoaffinity analogues of HMBPP, meta/para-benzophenone-(methylene)-prenyl pyrophosphates (m/p-BZ-(C)-C(5)-OPP), can crosslink to the surface of tumor cell lines and be presented as Ags to gammadelta T cells. Mutant tumor cell lines lacking MHC class I, MHC class II, beta(2)-microglobulin, and CD1, as well as tumor cell lines from a variety of tissues and individuals, will all crosslink to and present m-BZ-C(5)-OPP. Finally, pulsing of BZ-(C)-C(5)-OPP is inhibited by isopentenyl pyrophosphate and an inactive analog, suggesting that they bind to the same molecule. Taken together, these results suggest that nonpeptide Ags are presented by a novel-Ag-presenting molecule that is widely distributed and nonpolymorphic, but not classical MHC class I, MHC class II, or CD1.
Vγ2Vδ2 T细胞是人类外周血γδ T细胞的主要亚群，在感染过程中通过识别小分子非肽类异戊烯焦磷酸而扩增。这些分子包括微生物类异戊二烯中间体（E）-4-羟基-3-甲基-丁-2-烯基焦磷酸（HMBPP）和内源性类异戊二烯中间体异戊烯焦磷酸。这些非肽抗原的识别由Vγ2Vδ2 T细胞抗原受体介导。多项研究结果表明，异戊烯焦磷酸由一种抗原呈递分子呈递：T细胞与抗原呈递细胞之间需要接触，抗原不直接结合Vγ2Vδ2 TCR，并且在远离假定抗原识别位点的互补决定区中的TCR突变可消除抗原识别。然而，由于无法实现非肽类异戊烯焦磷酸抗原与呈递分子的稳定结合，阻碍了对假定抗原呈递分子的鉴定。在本研究中，我们表明HMBPP的光亲和类似物，间/对苯甲酮-（亚甲基）-异戊烯焦磷酸（m/p-BZ-(C)-C(5)-OPP），可以与肿瘤细胞系表面交联，并作为抗原呈递给γδ T细胞。缺乏MHC I类、MHC II类、β2-微球蛋白和CD1的突变肿瘤细胞系，以及来自各种组织和个体的肿瘤细胞系，都将与m-BZ-C(5)-OPP交联并呈递。最后，异戊烯焦磷酸和一种无活性类似物可抑制BZ-(C)-C(5)-OPP的脉冲，表明它们结合到同一分子上。综上所述，这些结果表明非肽抗原由一种新型抗原呈递分子呈递，该分子广泛分布且无多态性，但不是经典的MHC I类、MHC II类或CD1。
