Offner H, Malotky M K, Pope L, Vainiene M, Celnik B, Miller S D, Vandenbark A A
Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97201.
J Immunol. 1995 Jan 15;154(2):928-35.
The ability of synthetic V region peptides to induce regulatory T cells and Abs in rodents and humans provides clear evidence that these idiotopes do not naturally induce tolerance. In this study, we investigated the ability of TCR V beta 8.2 peptides to experimentally induce specific T cell tolerance, as measured by loss of Ag-specific proliferation and delayed-type hypersensitivity responses, and by increased susceptibility to experimental autoimmune encephalomyelitis (EAE). We found that both neonatal and adult exposure to V beta 8.2-39-59 or V beta 8-44-54 peptides could induce efficient T cell tolerance, resulting in a significant inhibition of peptide-specific proliferative responses. In addition, neonatal tolerance resulted in a partial reduction in delayed-type hypersensitivity response and an inability to vaccinate against EAE after adult immunization with the tolerizing peptide. We further evaluated the contribution of naturally induced TCR-specific responses to EAE resistance induced by challenging neonatally or adult tolerized rats with myelin basic protein in adjuvant. The clinical course of EAE was not significantly altered in rats tolerized neonatally to V beta 8.2 peptides, but both the severity and incidence of mortality from EAE was increased in rats tolerized as adults with V beta 8.2 peptides conjugated to syngeneic splenocytes. These results demonstrate that V beta 8.2 peptides are tolerogenic as well as immunogenic. Moreover, the observation of different effects of neonatal vs adult tolerization on the course of EAE suggests either the emergence of additional protective idiotopes after neonatal tolerization and/or mechanistic differences in the two tolerance-inducing protocols. Most importantly, the enhancement of clinical EAE in rats tolerized as adults with V beta 8.2 peptides provides evidence for an innate regulatory role of the CDR2 idiotope in recovery from EAE.
合成的V区肽在啮齿动物和人类中诱导调节性T细胞和抗体的能力提供了明确的证据，表明这些独特型不会自然诱导耐受性。在本研究中，我们研究了TCR Vβ8.2肽通过抗原特异性增殖丧失和迟发型超敏反应以及对实验性自身免疫性脑脊髓炎（EAE）易感性增加来实验性诱导特异性T细胞耐受性的能力。我们发现，新生和成年期暴露于Vβ8.2 - 39 - 59或Vβ8 - 44 - 54肽均可诱导有效的T细胞耐受性，导致肽特异性增殖反应受到显著抑制。此外，新生期耐受性导致迟发型超敏反应部分降低，并且在用耐受肽进行成年免疫后无法接种EAE疫苗。我们进一步评估了自然诱导的TCR特异性反应对用佐剂中的髓鞘碱性蛋白攻击新生或成年耐受大鼠所诱导的EAE抗性的贡献。新生期耐受Vβ8.2肽的大鼠中EAE的临床病程没有显著改变，但成年期用与同基因脾细胞偶联的Vβ8.2肽耐受的大鼠中EAE的严重程度和死亡率均增加。这些结果表明Vβ8.2肽具有耐受性和免疫原性。此外，新生期与成年期耐受对EAE病程的不同影响的观察表明，新生期耐受后可能出现额外的保护性独特型和/或两种耐受诱导方案的机制差异。最重要的是，成年期用Vβ8.2肽耐受的大鼠中临床EAE的增强为CDR2独特型在EAE恢复中的固有调节作用提供了证据。
