Department of Bioengineering, Imperial College London, London, UK.
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J R Soc Interface. 2021 Dec;18(185):20210464. doi: 10.1098/rsif.2021.0464. Epub 2021 Dec 1.
Swelling of lymph nodes (LNs) is commonly observed during the adaptive immune response, yet the impact on T cell (TC) trafficking and subsequent immune response is not well known. To better understand the effect of macro-scale alterations, we developed an agent-based model of the LN paracortex, describing the TC proliferative response to antigen-presenting dendritic cells alongside inflammation-driven and swelling-induced changes in TC recruitment and egress, while also incorporating regulation of the expression of egress-modulating TC receptor sphingosine-1-phosphate receptor-1. Analysis of the effector TC response under varying swelling conditions showed that swelling consistently aided TC activation. However, subsequent effector CD8 TC production was reduced in scenarios where swelling occurred too early in the TC proliferative phase or when TC cognate frequency was low due to increased opportunity for TC exit. Temporarily extending retention of newly differentiated effector TCs, mediated by sphingosine-1-phosphate receptor-1 expression, mitigated any negative effects of swelling by allowing facilitation of activation to outweigh increased access to exit areas. These results suggest that targeting temporary effector TC retention and egress associated with swelling offers new ways to modulate effector TC responses in, for example, immuno-suppressed patients and to optimize of vaccine design.
淋巴结（LNs）肿胀在适应性免疫反应中很常见，但它对 T 细胞（TC）迁移和随后的免疫反应的影响尚不清楚。为了更好地了解宏观变化的影响，我们开发了一个 LN 皮层的基于代理的模型，该模型描述了 TC 对呈递抗原的树突状细胞的增殖反应，以及炎症驱动和肿胀诱导的 TC 募集和迁出变化，同时还纳入了调节迁出调节 TC 受体鞘氨醇-1-磷酸受体-1 表达的规则。在不同肿胀条件下对效应 TC 反应的分析表明，肿胀始终有助于 TC 激活。然而，在 TC 增殖阶段早期发生肿胀或由于 TC 同源频率因 TC 出口机会增加而降低的情况下，随后的效应 CD8 TC 产生减少。通过表达鞘氨醇-1-磷酸受体-1 介导的新分化效应 TC 的暂时保留，通过允许激活的促进超过增加进入出口区域的机会，减轻了肿胀的任何负面影响。这些结果表明，靶向与肿胀相关的临时效应 TC 保留和迁出为调节免疫抑制患者中的效应 TC 反应和优化疫苗设计提供了新方法。
