Mast Cell Functions Linking Innate Sensing to Adaptive Immunity

Abstract

Although mast cells (MCs) are known as key drivers of type I allergic reactions, there is increasing evidence for their critical role in host defense. MCs not only play an important role in initiating innate immune responses, but also influence the onset, kinetics, and amplitude of the adaptive arm of immunity or fine-tune the mode of the adaptive reaction. Intriguingly, MCs have been shown to affect T-cell activation by direct interaction or indirectly, by modifying the properties of antigen-presenting cells, and can even modulate lymph node-borne adaptive responses remotely from the periphery. In this review, we provide a summary of recent findings that explain how MCs act as a link between the innate and adaptive immunity, all the way from sensing inflammatory insult to orchestrating the final outcome of the immune response.

Keywords: T cell; adaptive immunity; antigen presentation; dendritic cell; mast cell.

Figure 1

Peripheral mast cells (MCs) orchestrate the induction and amplitude of local innate responses and distant lymph node-borne adaptive immunity. The sensing of pathogens or danger-associated patterns by MCs or MC activation by IgE crosslinking in the periphery may result in MC degranulation and/or the de novo synthesis of pro-inflammatory mediators. Peripheral MCs exert remote effects on lymph node (LN) hypertrophy via histamine, TNF, and the drainage of intact MC secretory granules. The migration, maturation, and antigen-presenting capacity of dendritic cells (DCs) is promoted by MC soluble mediators, secretory granules, and exosomes, thereby facilitating T-cell expansion in draining LNs (DLNs). Finally, MCs enhance the homing of effector T cells to peripheral sites of inflammation/infection and may contribute to effector T-cell activation.

Figure 2

MCs impact T-cell activation by modulating DC functionality. MCs communicate with DCs in three different modes. (A) Soluble MC mediators, in particular histamine and TNF, promote the migration, maturation, and antigen-presenting capacity of DCs, thereby enhancing T-cell priming and fine-tuning T_H cell polarization. (B) MC exosomes and intact MC secretory granules, engulfed by DCs upon MC degranulation, facilitate DC migration and maturation, and consequently, boost T-cell priming. In turn, DCs relay antigen to MCs via extracellular microvesicles and thereby induce MC degranulation (C) MCs and DCs undergo dynamic physical interactions and synapse formation allowing bidirectional exchange. MCs transfer endocytosed antigen-IgE-FcεRI complexes to DCs, facilitating the activation of allergen-specific T cells. In turn, MCs are “cross-dressed” by DCs with MHCII complexes, thereby enabling the activation of effector T cells by MCs with antigen processed by DCs.

Figure 3

MC accumulation in LN T-cell zones upon immunization. Two-photon-microscopy of MC/T-cell double reporter mice revealed the accumulation of MCs in the T-cell zone and colocalization with T cells in inguinal LNs six days after intradermal immunization with collagen/CFA. Green: T cells; purple: MCs; blue: vessel tracer Angiospark 750; and yellow: anti-CD31Ab (quantification and more detailed information in [102]).

Figure 4

Direct role for MCs in the activation and modulation of T-cell responses. There is increasing evidence that MCs contribute to T-cell activation, not only by direct antigen-presenting potential, but also by modifying the outcome of the T-cell response. (A) Direct MC/T-cell interaction and synapse formation and the antigen-presenting capacity of MCs have been shown for CD4⁺ αβ T cells, γδ T cells, and CD8⁺ T cells. (B) Beyond direct activation, MCs can modulate T-cell activation by exosomes and soluble mediators. Here, MCs skew T-cell polarization towards Th1, Th17, or Th2, depending on the mode of MC stimulation. In addition, MCs provide anti-inflammatory effects by promoting T_reg activation via IL-2 or by inhibiting conventional T-cell activation via IL-10 in a T_reg-independent way.