Blockade of immune checkpoint receptors has shown outstanding efficacy for tumor immunotherapy. Promising treatment with anti-lymphocyte-activation gene-3 (LAG-3) has already been recognized as the next efficacious treatment, but there is still limited understanding of the mechanism of LAG-3-mediated immune suppression. Here, utilizing high-resolution molecular imaging, we find a mechanism of CD4 T cell suppression via LAG-3, in which LAG-3-bound major histocompatibility complex (MHC) class II molecules on antigen-presenting cells (APCs) gather at the central region of an immunological synapse and are trans-endocytosed by T cell receptor-driven internalization motility toward CD4 and CD8 T cells expressing LAG-3. Downregulation of MHC class II molecules on APCs thus results in the attenuation of their antigen-presentation function and impairment of CD4 T cell activation. From these data, anti-LAG-3 treatment is suggested to have potency to directly block the inhibitory signaling via LAG-3 and simultaneously reduce MHC class II expression on APCs by LAG-3-mediated trans-endocytosis for recovery from T cell exhaustion.
A 36-year-old woman was examined by our hospital for pulmonary coin shadows in both lungs, as disclosed on chest X-ray films. She had no subjective complaints other than allergic rhinitis, but exhibited hypergam-maglobulinemia, particularly in IgE. Inhalative allergen tests were positive for three types of allergens, but no autoimmune disease was detected. Although transbronchial and percutaneous fine needle biopsies failed to obtain enough specimens because of the wandering shadow a thoracoscopic biopsy was effective because of the subpleural location of the target lesions. The histologic findings were consistent with pulmonary hyalinizing granuloma, with extensive, hyalinized lamellar collagen bundles arranged haphazardly in the central area. Infiltration by lymphocytes and plasma cells, together with the destruction of bronchiolar and vessel walls, were observed in the marginal areas. No amyloid deposits or lymphocytic monoclonality were observed in the lesion. Twenty-five months after the biopsy, the patient's clinical and radiographic data had not changed.
Abstract NK cells express FcγRIII (CD16), which is responsible for IgG-dependent cell cytotoxicity and for production of several cytokines and chemokines. Whereas FcγRIII on NK cells is composed of both FcγRIIIα and FcRγ chains, that on mast cells is distinct from NK cells and made of FcγRIIIα, FcRβ, and FcRγ. Mast cells show degranulation and release several mediators, which cause anaphylactic responses upon cross-linking of FcγRIII as well as FcεRI with aggregated IgE. In this paper, we examined whether IgE activates NK cells through FcγRIII on their cell surface. We found that NK cells produce several cytokines and chemokines related to an allergic reaction upon IgE stimulation. Furthermore, NK cells exhibited cytotoxicity against IgE-coated target cells in an FcγRIII-dependent manner. These effects of IgE through FcγRIII were not observed in NK cells from FcRγ-deficient mice lacking FcγRIII expression. Collectively, these results demonstrate that NK cells can be activated with IgE through FcγRIII and exhibit both cytokine/chemokine production and Ab-dependent cell cytotoxicity. These data imply that not only mast cells but also NK cells may contribute to IgE-mediated allergic responses.
Abstract With recent advances in immune checkpoint inhibitors (ICIs), cancer immunotherapy has become the standard treatment for various malignant tumors. Their indications and dosages have been determined on the basis of several clinical trials conducted separately. In this study, we have established an advanced imaging system to visualize “human PD-1 microclusters,” in which PD-1 actually dephosphorylates both the TCR/CD3 complex and its downstream signaling molecules via the recruitment of a phosphatase, SHP2. Furthermore, each antibody required its own concentration and gained much greater effects in combination with other antibodies against different targets. We propose that our imaging system could digitally evaluate the PD-1-mediated T cell suppression and practical effects of each ICI. Currently, numerous new ICIs are tested, and more suitable combinations of them with other ICIs or conventional cancer treatments are being explored. Our study will have a wide range of applications to clinical practice in the future.
Summary: T‐cell activation requires contact between T cells and antigen‐presenting cells (APCs) to bring T‐cell receptors (TCRs) and major histocompatibility complex peptide (MHCp) together to the same complex. These complexes rearrange to form a concentric circular structure, the immunological synapse (IS). After the discovery of the IS, dynamic imaging technologies have revealed the details of the IS and provided important insights for T‐cell activation. We have redefined a minimal unit of T‐cell activation, the ‘TCR microcluster’, which recognizes MHCp, triggers an assembly of assorted molecules downstream of the TCR, and induces effective signaling from TCRs. The relationship between TCR signaling and costimulatory signaling was analyzed in terms of the TCR microcluster. CD28, the most valuable costimulatory receptor, forms TCR–CD28 microclusters in cooperation with TCRs, associates with protein kinase C θ, and effectively induces initial T‐cell activation. After mature IS formation, CD28 microclusters accumulate at a particular subregion of the IS, where they continuously assemble with the kinases and not TCRs, and generate sustained T‐cell signaling. We propose here a ‘TCR–CD28 microcluster’ model in which TCR and costimulatory microclusters are spatiotemporally formed at the IS and exhibit fine‐tuning of T‐cell responses by assembling with specific players downstream of the TCR and CD28.
