High avidity CD8+ T cells efficiently eliminate motile HIV-infected targets and execute a locally focused program of anti-viral function.
High avidity CD8+ T cells efficiently eliminate motile HIV-infected targets and execute a locally focused program of anti-viral function.
复制标题
DOI：
10.1371/journal.pone.0087873
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Irvine DJ
中科院分区：
文献类型：
--
作者：
Foley MH;Forcier T;McAndrew E;Gonzalez M;Chen H;Juelg B;Walker BD;Irvine DJ
移动的HIV感染的CD4+ t细胞促进了HIV从最初感染部位的传播。然而，受感染的靶细胞迁移对hiv特异性CD8+ t细胞抗原识别的影响尚不清楚。利用体外组织3D模型，我们可视化了hiv感染或肽脉冲CD4+ t细胞与hiv特异性CD8+ t细胞之间的动态相互作用。ctl攻击移动的hiv感染目标，但约50%的目标脱离接触并逃脱。相反，固定的靶细胞很容易被杀死，这表明靶细胞的运动性直接抑制CD8+ t细胞的功能。强钙信号发生在杀死运动靶标的ctl中，但钙信号微弱或不存在于允许靶标逃逸的ctl中。粘附受体LFA-1和CD58的中和抑制了3D基质内CD8+ t细胞的功能，表明有效的运动靶标裂解依赖于靶标的粘附作用。抗原敏感性（抗原密度、TCR亲和度和CD8辅助受体结合的卷积）对靶标识别也至关重要。我们通过利用常见的HIV逃逸突变并在单细胞水平上测量它们对CTL功能的影响来调节该参数（称为功能亲和度，但为了简单起见，此处称为“亲和度”）。低贪婪突变抗原脉冲的靶标经常逃脱，而ctl以近乎完美的效率杀死了高贪婪抗原的靶标。ctl在几分钟内攻击、逮捕并杀死一个携带高贪婪抗原的初始目标，但连环杀伤却令人惊讶地罕见。CD8细胞在最初的死亡靶标上停留数小时，积累TCR信号，持续分泌可溶性抗病毒因子。这些数据表明，高亲和力的CD8+ t细胞在抗原被感知的精确位置执行抗病毒程序：CTL效应功能在时空上与早期裂解期协调，随后是持续的静止分泌期，以控制局部病毒感染。
The dissemination of HIV from an initial site of infection is facilitated by motile HIV-infected CD4+ T-cells. However, the impact of infected target cell migration on antigen recognition by HIV-specific CD8+ T-cells is unclear. Using a 3D in vitro model of tissue, we visualized dynamic interactions between HIV-infected or peptide-pulsed CD4+ T-cells and HIV-specific CD8+ T-cells. CTLs engaged motile HIV-infected targets, but ∼50% of targets broke contact and escaped. In contrast, immobilized target cells were readily killed, indicating target motility directly inhibits CD8+ T-cell function. Strong calcium signals occurred in CTLs killing a motile target but calcium signaling was weak or absent in CTLs which permitted target escape. Neutralization of adhesion receptors LFA-1 and CD58 inhibited CD8+ T-cell function within the 3D matrix, demonstrating that efficient motile target lysis as dependent on adhesive engagement of targets. Antigen sensitivity (a convolution of antigen density, TCR avidity and CD8 coreceptor binding) is also critical for target recognition. We modulated this parameter (known as functional avidity but referred to here as “avidity” for the sake of simplicity) by exploiting common HIV escape mutations and measured their impact on CTL function at the single-cell level. Targets pulsed with low avidity mutant antigens frequently escaped while CTLs killed targets bearing high avidity antigen with near-perfect efficiency. CTLs engaged, arrested, and killed an initial target bearing high avidity antigen within minutes, but serial killing was surprisingly rare. CD8 cells remained committed to their initial dead target for hours, accumulating TCR signals that sustained secretion of soluble antiviral factors. These data indicate that high-avidity CD8+ T-cells execute an antiviral program in the precise location where antigen has been sensed: CTL effector functions are spatiotemporally coordinated with an early lytic phase followed by a sustained stationary secretory phase to control local viral infection.
登录
查看更多内容
DOI：
10.1084/jem.20061890
发表时间：
2007-02-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Boissonnas A;Fetler L;Zeelenberg IS;Hugues S;Amigorena S
通讯作者：
Amigorena S
DOI：
10.1084/jem.20070784
发表时间：
2007-10-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Almeida JR;Price DA;Papagno L;Arkoub ZA;Sauce D;Bornstein E;Asher TE;Samri A;Schnuriger A;Theodorou I;Costagliola D;Rouzioux C;Agut H;Marcelin AG;Douek D;Autran B;Appay V
通讯作者：
Appay V
影响因子：
4.4
作者：
Faroudi, M;Zaru, R;Valitutti, S
通讯作者：
Valitutti, S
影响因子：
8
作者：
Genesca, M.;Skinner, P. J.;Miller, C. J.
通讯作者：
Miller, C. J.
影响因子：
5.4
作者：
ISAAZ, S;BAETZ, K;GRIFFITHS, GM
通讯作者：
GRIFFITHS, GM