Rist Michael, Smith Corey, Bell Melissa J, Burrows Scott R, Khanna Rajiv
Australian Centre for Vaccine Development and Tumour Immunology Laboratory, Division of Infectious Immunology, Queensland Institute of Medical Research, Brisbane, Australia.
Blood. 2009 Sep 10;114(11):2244-53. doi: 10.1182/blood-2009-05-222596. Epub 2009 Jul 17.
The ability of CD8(+) T cells to engage a diverse range of peptide-major histocompatibility complex (MHC) complexes can also lead to cross-recognition of self and nonself peptide-MHC complexes and thus directly contribute toward allograft rejection or autoimmunity. Here we present a novel form of cross-recognition by herpes virus-specific CD8(+) cytotoxic T cells that challenges the current paradigm of self/non-self recognition. Functional characterization of a human leukocyte antigen (HLA) Cw0602-restricted cytomegalovirus-specific CD8(+) T-cell response revealed an unusual dual specificity toward a pp65 epitope and the alloantigen HLA DR4. This cross-recognition of HLA DR4 alloantigen was critically dependent on the coexpression of HLA DM and was preferentially directed toward the B-cell lineage. Furthermore, allostimulation of peripheral blood lymphocytes with HLA DRB0401-expressing cells rapidly expanded CD8(+) T cells, which recognized the pp65 epitope in the context of HLA Cw*0602. T-cell repertoire analysis revealed 2 dominant populations expressing T-cell receptor beta variable (TRBV)4-3 or TRBV13, with cross-reactivity exclusively mediated by the TRBV13(+) clonotypes. More importantly, cross-reactive TRBV13(+) clonotypes displayed markedly lower T-cell receptor binding affinity and a distinct pattern of peptide recognition, presumably mimicking a structure presented on the HLA DR4 allotype. These results illustrate a novel mechanism whereby virus-specific CD8(+) T cells can cross-recognize HLA class II molecules and may contribute toward allograft rejection and/or autoimmunity.
CD8(+) T细胞与多种肽 - 主要组织相容性复合体（MHC）复合体结合的能力，也可能导致对自身和非自身肽 - MHC复合体的交叉识别，从而直接促成同种异体移植排斥或自身免疫。在此，我们展示了疱疹病毒特异性CD8(+) 细胞毒性T细胞的一种新型交叉识别形式，它挑战了当前的自身/非自身识别范式。对人白细胞抗原（HLA）Cw0602限制性巨细胞病毒特异性CD8(+) T细胞应答的功能特性分析显示，其对pp65表位和同种异体抗原HLA DR4具有不同寻常的双重特异性。这种对HLA DR4同种异体抗原的交叉识别严重依赖于HLA DM的共表达，且优先针对B细胞谱系。此外，用表达HLA DRB0401的细胞对外周血淋巴细胞进行同种异体刺激，可迅速扩增CD8(+) T细胞，这些细胞在HLA Cw*0602背景下识别pp65表位。T细胞库分析显示，有两个优势群体表达T细胞受体β可变区（TRBV）4 - 3或TRBV13，交叉反应仅由TRBV13(+) 克隆型介导。更重要的是，交叉反应性TRBV13(+) 克隆型显示出明显更低的T细胞受体结合亲和力和独特的肽识别模式（可能模拟了HLA DR4同种异型上呈现的结构）。这些结果说明了一种新型机制，即病毒特异性CD8(+) T细胞可交叉识别HLA II类分子，可能促成同种异体移植排斥和/或自身免疫。
