Chou Y K, Morrison W J, Weinberg A D, Dedrick R, Whitham R, Bourdette D N, Hashim G, Offner H, Vandenbark A A
Veterans Affairs Medical Center, Portland, OR 97201.
J Immunol. 1994 Mar 1;152(5):2520-9.
The biased expression of V beta 5.2 and V beta 6.1 by T cells specific for myelin basic protein (BP) has led to our use of TCR peptides from these V gene sequences to induce anti-TCR immunity in patients with multiple sclerosis (MS). Injection of V beta 5.2-39-59 or V beta 6.1-39-59 peptides significantly increased the peptide specific T cell frequency in 7 of 11 MS patients, often with an accompanying delayed hypersensitivity reaction at the injection site. Here, we validate these cellular immune responses by characterizing TCR peptide specific T cells from an MS patient with biased V beta 5.2 expression in BP reactive T cells before treatment with TCR peptides, and from two MS patients in whom the frequencies of anti-TCR peptide specific T cells were significantly boosted after injection with low doses of TCR peptides. In both cases, T cell lines were established with relative ease, especially after boosting with the peptides. A V beta 5.2-39-59 reactive line responded selectively to the boosting peptide and was restricted by both MHC class I (HLA-B7) and MHC class II (HLA-DR2) molecules. Characterization of 22 clonal isolates revealed that the responding T cells were predominantly activated CD4+CD8lo, circulating memory cells restricted by either HLA-B7 or HLA-DR2, that utilized mainly V beta 4, V beta 6, V beta 12, and V beta 14, but not V beta 5.2 in their TCR. T cell isolates specific for V beta 6.1-39-59 possessed similar characteristics but contained specificities cross-reactive with an N-terminal sequence on V beta 5.2-39-59. Upon stimulation with peptide or Con A, the TCR peptide specific T cell lines had increased message production for IFN-gamma, GM-CSF, IL-4, IL-5, and to a lesser degree, IL-2. This lymphokine mRNA profile differed from a BP-specific T cell line that produced message for IFN-gamma and GM-CSF but low or absent levels of IL-4 and IL-5. The extensive parallels between human T cells specific for V beta 5.2 and V beta 6.1 CDR2 peptides and rat T cells specific for V beta 8.2 CDR2 peptide that are highly protective against experimental encephalomyelitis strengthen the rationale for the therapeutic use of TCR peptides in human autoimmunity.
针对髓鞘碱性蛋白（BP）的T细胞对Vβ5.2和Vβ6.1的偏向性表达，促使我们利用来自这些V基因序列的TCR肽，在多发性硬化症（MS）患者中诱导抗TCR免疫。注射Vβ5.2 - 39 - 59或Vβ6.1 - 39 - 59肽后，11例MS患者中有7例的肽特异性T细胞频率显著增加，注射部位常伴有迟发型超敏反应。在此，我们通过对一名在接受TCR肽治疗前BP反应性T细胞中Vβ5.2表达偏向的MS患者以及两名注射低剂量TCR肽后抗TCR肽特异性T细胞频率显著升高的MS患者的TCR肽特异性T细胞进行表征，来验证这些细胞免疫反应。在这两种情况下，T细胞系都相对容易建立，尤其是在用肽增强后。一个对Vβ5.2 - 39 - 59有反应的细胞系对增强肽有选择性反应，并受MHC I类（HLA - B7）和MHC II类（HLA - DR2）分子限制。对22个克隆分离株的表征显示，反应性T细胞主要是活化的CD4 + CD8lo循环记忆细胞，受HLA - B7或HLA - DR2限制，其TCR主要利用Vβ4、Vβ6、Vβ12和Vβ14，但不利用Vβ5.2。对Vβ6.1 - 39 - 59特异的T细胞分离株具有相似特征，但包含与Vβ5.2 - 39 - 59的N端序列交叉反应的特异性。在用肽或刀豆蛋白A刺激后，TCR肽特异性T细胞系中IFN - γ、GM - CSF、IL - 4、IL - 5以及程度较轻的IL - 2的信使产生增加。这种细胞因子mRNA谱不同于一个产生IFN - γ和GM - CSF信使但IL - 4和IL - 5水平低或无的BP特异性T细胞系。对Vβ5.2和Vβ6.1 CDR2肽特异的人T细胞与对Vβ8.2 CDR2肽特异的大鼠T细胞之间存在广泛相似性，后者对实验性脑脊髓炎具有高度保护作用，这加强了在人类自身免疫中使用TCR肽进行治疗的理论依据。
