Altered peptide ligands can modify the Th2 T cell response to the immunodominant 161-175 peptide of LACK (Leishmania homolog for the receptor of activated C kinase).
Altered peptide ligands can modify the Th2 T cell response to the immunodominant 161-175 peptide of LACK (Leishmania homolog for the receptor of activated C kinase).
复制标题
DOI：
10.1016/j.molimm.2008.10.024
复制
发表时间：
2009-01
影响因子：
3.6
通讯作者：
Gabaglia CR
中科院分区：
文献类型：
--
作者：
Jensen KD;Sercarz EE;Gabaglia CR
在L. major感染后，早期LACK（活化C激酶受体的利什曼原虫同源物）诱导的IL-4反应似乎决定了BALB/ C小鼠的疾病易感性。因此，我们试图利用改变的肽配体（apl）来操纵致病性T细胞对免疫显性表位的反应。在四种不同的缺乏反应性T细胞系统中，检测了LACK 161-175肽决定因子的每个氨基酸的保守和非保守替代的刺激能力。根据这些结果，我们提出了一个可能的LACK 163-171 /I-Ad核心肽寄存器，并表明在假定的T细胞受体（TCR）接触处发生变化的api提供了最大的免疫偏差可能性。特别是，tcr接触的H164V APL在体外召回来自缺乏特异性BV4 T细胞受体转基因小鼠的naïve脾细胞时扩增了Th1细胞，并刺激了th2承诺的lack反应性T细胞系的IFN-γ分泌。我们还观察到，核心决定因素两侧的非保守取代对增殖和Th1/Th2调节具有强烈的激动作用。然而，免疫后，H164V APL显著下调了对野生型LACK 161-175肽的增殖和细胞因子反应，而弱激动剂MHC接触APL S171K免疫可提高IFN-γ/IL-4对野生型肽的比例。在这些情况下，通过使用在TCR接触位点具有非保守取代的APL免疫来实现对野生型肽的低反应性T细胞应答，而使用保留核心决定因素的弱激动剂APL来实现免疫偏差。因此，某些lack - api能够在感染性疾病（如利什曼病）中诱导具有保护性表型的T细胞反应。
Following L. major infection, the early LACK (Leishmania homolog of receptors for activated C kinase)- induced IL-4 response appears to determine disease susceptibility in BALB/c mice. Therefore, we sought to manipulate the pathogenic T cell responses to the immunodominant epitope with the use of altered peptide ligands (APLs). Conservative and non-conservative substitutions for each amino acid of the LACK 161–175 peptide determinant were tested for their stimulatory capacity in four different LACK-reactive T cell systems. From these results, we propose a likely LACK 163–171/I-Ad core peptide register and show that APLs with changes at putative T cell receptor (TCR) contacts provide the greatest potential for immune deviation. In particular, the TCR-contact H164V APL expanded Th1 cells upon in vitro recall of naïve splenocytes from LACK-specific BV4 T cell receptor transgenic mice and stimulated IFN-γ secretion from a Th2-committed LACK-reactive T cell line. We also observed that non-conservative substitutions flanking the core determinant had strong agonistic effects for proliferation and Th1/Th2 modulation. However, upon immunization, the H164V APL considerably downregulated proliferation and cytokine responses to the wild type LACK 161–175 peptide, while immunization with the weak agonist, MHC contact APL S171K, increased the IFN-γ/IL-4 ratio to the wild type peptide. In these instances, a hyporesponsive T cell response to the wild-type peptide was achieved by immunizing with an APL possessing non-conservative substitutions at TCR contact sites, while immune deviation was accomplished using a weak-agonist APL that retained the core determinant. Thus, certain LACK-APLs are able to induce T cell responses with a protective phenotype in an infectious disease such as leishmaniasis.
登录
查看更多内容
法配体的改变揭示了T细胞对病原表位的响应中的可塑性有限。
影响因子：
15.3
作者：
Pingel, S;Launois, P;Fowell, D J;Turck, C W;Southwood, S;Sette, A;Glaichenhaus, N;Louis, J A;Locksley, R M
通讯作者：
Locksley, R M
影响因子：
56.9
作者：
HUNT, DF;MICHEL, H;SETTE, A
通讯作者：
SETTE, A
影响因子：
4.4
作者：
Arnold, PY;La Gruta, NL;Vignali, DAA
通讯作者：
Vignali, DAA
影响因子：
1.3
作者：
Myers, Linda K.;Tang, Bo;Kang, Andrew H.
通讯作者：
Kang, Andrew H.
DOI：
10.1073/pnas.92.21.9510
发表时间：
1995-10-10
影响因子：
11.1
作者：
KUMAR, V;BHARDWAJ, V;SERCARZ, E
通讯作者：
SERCARZ, E