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Signal-transducing adaptor protein-2 (STAP-2) is a unique scaffold protein that regulates several immunological signaling pathways, including LIF/LIF receptor and LPS/TLR4 signals. STAP-2 is required for Fas/FasL-dependent T cell apoptosis and SDF-1α-induced T cell migration. Conversely, STAP-2 modulates integrin-mediated T cell adhesion, suggesting that STAP-2 is essential for several negative and positive T cell functions. However, whether STAP-2 is involved in T cell-antigen receptor (TCR)-mediated T cell activation is unknown. STAP-2 deficiency was recently reported to suppress TCR-mediated T cell activation by inhibiting LCK-mediated CD3ζ and ZAP-70 activation. Using STAP-2 deficient mice, it was demonstrated that STAP-2 is required for the pathogenesis of Propionibacterium acnes-induced granuloma formation and experimental autoimmune encephalomyelitis. Here, detailed functions of STAP-2 in TCR-mediated T cell activation, and how STAP-2 affects the pathogenesis of T cell-mediated inflammation and immune diseases, are reviewed.

Mast cells are effector cells in immunoglobulin E (IgE)-mediated immediate hypersensitivity and allergic diseases such as asthma and food allergy. Mast cells are activated by the aggregation of the IgE-bound high-affinity IgE receptor FcεRI with multivalent antigen. Activated mast cells secrete proinflammatory mediators such as histamine, serotonin, and proteases and produce cytokines and chemokines. However, it has been reported that mast cells are activated by crosslinking of FcεRI with monomeric IgE in the absence of antigen. We have recently demonstrated that histamine-releasing factor (HRF) is involved in IgE-mediated mast cell activation both in vitro and in vivo. HRF binds to a subset of IgE and IgG molecules [HRF-reactive antibodies (Abs)]. The Fab, but not Fc, portions of the IgE and IgG molecules are HRF-binding sites, and the N-terminal 19-residue (N19) and H3 portions of HRF are HRF-reactive Ab-binding sites. We observed that both N19 and H3 tagged with glutathione S transferase (GST) (GST-N19 and GST-H3) can inhibit the interaction between HRF and HRF-reactive Abs. Using acute- and late-phase passive cutaneous anaphylaxis mouse models, it was shown that HRF initiates mast cell activation through HRF-reactive, but not HRF-nonreactive, IgE in vivo. Antigen-induced passive cutaneous anaphylaxis was inhibited by pretreatment with GST-N19 and GST-H3. We demonstrated that pretreatment with GST-N19 before antigen challenge inhibited antigen-induced mast cell-dependent airway inflammation. In addition, GST-N19 partially inhibited Aspergillus fumigatus extract-induced IgE-dependent airway inflammation. However, GST-N19 did not inhibit T cell-dependent airway inflammation. These results suggest that mast cells are target cells for HRF to initiate IgE- and mast cell-dependent airway inflammation.