T Cell Motility as Modulator of Interactions with Dendritic Cells

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.

Keywords: Myo1g; T cell motility; T cell–DC interactions; intravital imaging; thromboxane A2.

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.