Mast cells and T-cell expansion

Mast cells (MCs) are responsible for host defenses against bacterial, viral, and parasitic infection through the activation of complement-mediated or Toll-like receptor (TLR)–mediated innate immune responses and IgE/antigen-FcϵRI–mediated acquired immune responses.¹  However, excessive or inappropriate MC activation also contributes to the development of certain allergic or autoimmune diseases, which are mediated by allergen- or autoantigen-specific effector T cells.¹ 

MCs are capable of presenting antigens to T cells by direct cell-cell interaction through antigen-specific T-cell receptor (TCR) and major histocompatibility complex (MHC) class I– or class II–restricted mechanisms in vitro.¹  Exosomes released from MCs, which contain MHC class II and antigen complexes, participate in antigen-specific T-cell expansion/activation independently of direct cell-cell contact between T cells and MCs in vitro.¹  However, it has remained unclear whether MCs have such functions in vivo.

In the February 1 issue of Blood, Kambayashi and coworkers provided a novel molecular mechanism for MHC class II–restricted, antigen-specific T-cell expansion/activation by murine bone marrow–derived cultured MCs (BMCMCs) in a series of well-designed and elegant experiments. Consistent with prior work,²  they demonstrated that naive BMCMCs showed poor antigen-presenting capabilities to CD4⁺ T cells from MHC class II–restricted and the ovalbumin (OVA)-specific TCR-transgenic (OTII) stain. However, MHC class II–deficient BMCMCs stimulated in advance with anti-OVA IgE and OVA were found to clearly facilitate OTII T-cell activation without further addition of OVA. In addition, IgE/antigen-FcϵRI crosslinking enhanced the internalization of IgE/antigen complexes in MCs, and induced MC apoptosis by down-modulating Bcl-XL expression. The authors also demonstrated that apoptotic MCs carrying intracellularly incorporated antigens were phagocytosed by dendritic cells (DCs). Then, DCs processed the MC-derived intracellular antigens, presented them to CD4⁺ T cells, and thus induced the expansion/activation of antigen-specific T cells (see figure). These findings suggest that MCs can work as antigen reservoirs and can act as “bridging cells” that transfer the antigen to potent antigen-presenting cells such as DCs.

MCs exist in close proximity with T cells in human tonsils³  as well as at the inflammatory sites in mice,²  and in close proximity with DCs in most tissues.⁴  In addition, MCs can migrate into draining lymph nodes from antigen entry sites.⁵  Based on the present work by Kambayashi and coworkers, it is possible that IgE/antigen-captured MCs become apoptotic in T-cell zones¹  in secondary lymphoid tissues and/or at antigen-challenged inflammatory sites. Thus, DCs can present MC-derived antigens to “antigen-specific,” that is, already antigen-sensitized, memory T helper cells. In contrast to a previous report indicating that MC-mediated T-cell activation is Ig/antigen-FcR independent,²  the findings of Kambayashi and colleagues indicate that MC-mediated T-cell activation is dependent on IgE, and thus it cannot be adopted for less/non-IgE–mediated diseases such as autoimmune disorders. Nevertheless, the present findings provide new insight into our understanding of the molecular mechanisms in-volved in the development of IgE- and MC-mediated allergic diseases.