SHP-1 phosphatase activity counteracts increased T cell receptor affinity
SHP-1 phosphatase activity counteracts increased T cell receptor affinity
复制标题
DOI：
10.1172/jci65325
复制
发表时间：
2013-03-01
影响因子：
15.9
通讯作者：
Rufer, Nathalie
中科院分区：
文献类型：
--
作者：
Hebeisen, Michael;Baitsch, Lukas;Rufer, Nathalie
通过在生理限度内增加TCR-肽MHC（pMHC）亲和力可以改善抗自身/肿瘤T细胞功能，但矛盾的是，进一步增加（K-d < 1 μ M）会导致功能急剧下降。我们使用人类CD 8（+）T细胞，这些细胞被改造成具有对肿瘤抗原HLA-A2/NY-ESO-1的递增亲和力的TCR，研究了这种高亲和力相关功能丧失的分子机制。与表达产生最佳功能的TCR亲和力的细胞（Kd = 5至1 μ M）相比，具有超生理亲和力的细胞（Kd = 1 μ M至15 nM）显示出受损的基因表达、信号传导和活化/共刺激受体的表面表达。抑制性受体程序性细胞死亡-1（PD-1）的优先表达仅限于具有最高TCR亲和力的T细胞，与PD-1配体后的完全功能恢复相关。1（PD-L1）阻断。相反，上调的Src同源2结构域的磷酸酶1（SHP-1/PTPN 6）是广泛的，随着TCR亲和力的增加，在CD 8 + T细胞中的表达逐渐增强。因此，用葡萄糖酸锑钠对SHP-1的药理学抑制增强了所有工程化T细胞的功能，这与SHP-1的TCR亲和力依赖性水平相关。这些数据突出了SHP-1在调节CD 8（+）T细胞活化和反应性中的意想不到的和全局性的作用，并支持抑制蛋白酪氨酸磷酸酶以增强T细胞介导的免疫的疗法的开发。
Anti-self/tumor T cell function can be improved by increasing TCR-peptide MHC (pMHC) affinity within physiological limits, but paradoxically further increases (K-d < 1 mu M) lead to drastic functional declines. Using human CD8(+) T cells engineered with TCRs of incremental affinity for the tumor antigen HLA-A2/NY-ESO-1, we investigated the molecular mechanisms underlying this high-affinity-associated loss of function. As compared with cells expressing TCR affinities generating optimal function (K-d = 5 to 1 mu M), those with supraphysiological affinity (K-d = 1 mu M to 15 nM) showed impaired gene expression, signaling, and surface expression of activatory/costimulatory receptors. Preferential expression of the inhibitory receptor programmed cell death-1 (PD-1) was limited to T cells with the highest TCR affinity, correlating with full functional recovery upon PD-1 ligand. 1 (PD-L1) blockade. In contrast, upregulation of the Src homology 2 domain-containing phosphatase 1 (SHP-1/PTPN6) was broad, with gradually enhanced expression in CD8+ T cells with increasing TCR affinities. Consequently, pharmacological inhibition of SHP-1 with sodium stibogluconate augmented the function of all engineered T cells, and this correlated with the TCR affinity-dependent levels of SHP-1. These data highlight an unexpected and global role of SHP-1 in regulating CD8(+) T cell activation and responsiveness and support the development of therapies inhibiting protein tyrosine phosphatases to enhance T cell-mediated immunity.