Abstract
It is well established that the balance of costimulatory and inhibitory signals during interactions with dendritic cells (DCs) determines T cell transition from a naïve to an activated or tolerant/anergic status. Although many of these molecular interactions are well reproduced in reductionist in vitro assays, the highly dynamic motility of naïve T cells in lymphoid tissue acts as an additional lever to fine-tune their activation threshold. T cell detachment from DCs providing suboptimal stimulation allows them to search for DCs with higher levels of stimulatory signals, while storing a transient memory of short encounters. In turn, adhesion of weakly reactive T cells to DCs presenting peptides presented on major histocompatibility complex with low affinity is prevented by lipid mediators. Finally, controlled recruitment of CD8+ T cells to cognate DC–CD4+ T cell clusters shapes memory T cell formation and the quality of the immune response. Dynamic physiological lymphocyte motility therefore constitutes a mechanism to mitigate low avidity T cell activation and to improve the search for “optimal” DCs, while contributing to peripheral tolerance induction in the absence of inflammation.
Highlights
It is well established that the balance of costimulatory and inhibitory signals during interactions with dendritic cells (DCs) determines T cell transition from a naïve to an activated or tolerant/anergic status
The LFA-1 ligands ICAM-1 and ICAM-2 are expressed on both DCs and fibroblastic reticular cells (FRCs), while CCL21 is deposited on DCs [14, 15]. 2PM imaging experiments have shown that CCR7 ligands and LFA-1–ICAM-1 interactions contribute to basal migration, even in their absence, T cells retain their amoeboid migration mode and attain considerable average speeds of ~10–12 μm/min [16,17,18,19]
Tightly regulated T cell attraction to activated DCs promote adaptive immune responses by allowing rare cells to meet, excessive interactions with low-affinity pMHCpresenting DCs deteriorate the overall quality of clonal expansion
Summary
It is well established that the balance of costimulatory and inhibitory signals during interactions with dendritic cells (DCs) determines T cell transition from a naïve to an activated or tolerant/anergic status. Many of these molecular interactions are well reproduced in reductionist in vitro assays, the highly dynamic motility of naïve T cells in lymphoid tissue acts as an additional lever to fine-tune their activation threshold. The dynamic motility has evolved because T cells are MHC restricted and need to physically scan the surfaces of other cells This process is balanced with rapid decision-making on whether to arrest (e.g., to exert cytotoxic activity against a target cell) or to continue migration. Decision-making of whether to “stop” or to “go” is probably most critical in lymphoid tissue, such as peripheral lymph nodes (PLNs), where T cells move with highest speeds and are only in short contact with pMHC-presenting dendritic cells (DCs)
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