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T Cell Motility as Modulator of Interactions with Dendritic Cells

View Article: PubMed Central

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.

No MeSH data available.


Related in: MedlinePlus

Motile T cell–DC interactions in lymphoid tissue. (A) Phases of interactions between pMHC-loaded DCs and T cells after their entry into lymph nodes. Phase 1 is characterized by transient interactions, whereas T cells engage stably with DCs during phase 2. In phase 3, T cells detach from DCs and begin to divide before egressing as effector T cells. Adapted from Ref. (55). (B) Regulation of weak T cell–DC interactions by TXA2 secretion. TP-induced motility prevents stable T cell attachment (phase 1–2 transition) unless a critical pMHC threshold is presented on DCs, thus ensuring a high quality of ensuing CD4+ T cell responses. (C) Secretion of CCR5 ligands CCL3 and CCL4 by pairs of interacting CD4+ T cells and DCs attract naïve CD8+ T cells and helps to foster CD4+ T cell help. By contrast, excessive CCR5 ligand production in the absence of Tregs deteriorates the quality of CD8+ T cell responses by allowing weakly interacting clones to attach to DCs.
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Figure 1: Motile T cell–DC interactions in lymphoid tissue. (A) Phases of interactions between pMHC-loaded DCs and T cells after their entry into lymph nodes. Phase 1 is characterized by transient interactions, whereas T cells engage stably with DCs during phase 2. In phase 3, T cells detach from DCs and begin to divide before egressing as effector T cells. Adapted from Ref. (55). (B) Regulation of weak T cell–DC interactions by TXA2 secretion. TP-induced motility prevents stable T cell attachment (phase 1–2 transition) unless a critical pMHC threshold is presented on DCs, thus ensuring a high quality of ensuing CD4+ T cell responses. (C) Secretion of CCR5 ligands CCL3 and CCL4 by pairs of interacting CD4+ T cells and DCs attract naïve CD8+ T cells and helps to foster CD4+ T cell help. By contrast, excessive CCR5 ligand production in the absence of Tregs deteriorates the quality of CD8+ T cell responses by allowing weakly interacting clones to attach to DCs.

Mentions: Two photon microscopy analysis has helped to subdivide T cell–DC interactions into distinct phases that are regulated by surface levels of pMHC on DCs, as well as the TCR–pMHC affinity. Thus, high levels of cognate pMHC are able to induce immediate arrest of reactive T cells, whereas low levels result in a continuous scanning behavior of T cells (47–49). During scanning, which can last up to 8 h and is referred to as “phase 1,” T cells are able to summate signals through active NFAT and c-fos signaling (50, 51). In addition to pMHC, ICAM-1 on DCs facilitates T cell arrest (52), whereas regulatory T cells (Tregs) prevent stable interactions with DCs in this phase (53, 54). “Phase 2” stable T cell–DC interactions last for several hours and are commonly thought to be critical for full T cell activation through the formation of an immunological synapse (IS). Thus far, the precise duration of individual stable T cell–DC contacts has proven difficult to assess in vivo, owing to technical limitations maintaining physiological conditions and the identical field of view during intravital imaging. After ~20 h post T cell transfer, activated T cells resume motility and detach from DCs before committing to cell division, in the so-called phase 3 (Figure 1A).


T Cell Motility as Modulator of Interactions with Dendritic Cells
Motile T cell–DC interactions in lymphoid tissue. (A) Phases of interactions between pMHC-loaded DCs and T cells after their entry into lymph nodes. Phase 1 is characterized by transient interactions, whereas T cells engage stably with DCs during phase 2. In phase 3, T cells detach from DCs and begin to divide before egressing as effector T cells. Adapted from Ref. (55). (B) Regulation of weak T cell–DC interactions by TXA2 secretion. TP-induced motility prevents stable T cell attachment (phase 1–2 transition) unless a critical pMHC threshold is presented on DCs, thus ensuring a high quality of ensuing CD4+ T cell responses. (C) Secretion of CCR5 ligands CCL3 and CCL4 by pairs of interacting CD4+ T cells and DCs attract naïve CD8+ T cells and helps to foster CD4+ T cell help. By contrast, excessive CCR5 ligand production in the absence of Tregs deteriorates the quality of CD8+ T cell responses by allowing weakly interacting clones to attach to DCs.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
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Figure 1: Motile T cell–DC interactions in lymphoid tissue. (A) Phases of interactions between pMHC-loaded DCs and T cells after their entry into lymph nodes. Phase 1 is characterized by transient interactions, whereas T cells engage stably with DCs during phase 2. In phase 3, T cells detach from DCs and begin to divide before egressing as effector T cells. Adapted from Ref. (55). (B) Regulation of weak T cell–DC interactions by TXA2 secretion. TP-induced motility prevents stable T cell attachment (phase 1–2 transition) unless a critical pMHC threshold is presented on DCs, thus ensuring a high quality of ensuing CD4+ T cell responses. (C) Secretion of CCR5 ligands CCL3 and CCL4 by pairs of interacting CD4+ T cells and DCs attract naïve CD8+ T cells and helps to foster CD4+ T cell help. By contrast, excessive CCR5 ligand production in the absence of Tregs deteriorates the quality of CD8+ T cell responses by allowing weakly interacting clones to attach to DCs.
Mentions: Two photon microscopy analysis has helped to subdivide T cell–DC interactions into distinct phases that are regulated by surface levels of pMHC on DCs, as well as the TCR–pMHC affinity. Thus, high levels of cognate pMHC are able to induce immediate arrest of reactive T cells, whereas low levels result in a continuous scanning behavior of T cells (47–49). During scanning, which can last up to 8 h and is referred to as “phase 1,” T cells are able to summate signals through active NFAT and c-fos signaling (50, 51). In addition to pMHC, ICAM-1 on DCs facilitates T cell arrest (52), whereas regulatory T cells (Tregs) prevent stable interactions with DCs in this phase (53, 54). “Phase 2” stable T cell–DC interactions last for several hours and are commonly thought to be critical for full T cell activation through the formation of an immunological synapse (IS). Thus far, the precise duration of individual stable T cell–DC contacts has proven difficult to assess in vivo, owing to technical limitations maintaining physiological conditions and the identical field of view during intravital imaging. After ~20 h post T cell transfer, activated T cells resume motility and detach from DCs before committing to cell division, in the so-called phase 3 (Figure 1A).

View Article: PubMed Central

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.

No MeSH data available.


Related in: MedlinePlus