Paper Reading
01
MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota
Motoko Koyama, PamelaMukhopadhyay, et al
Immunity,
Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract is the principal determinant of lethality following allogeneic bone marrow transplantation. Acute GVHD of the GI tract, the prima facie determinant of disease severity and lethality, is the manifestation of immunopathology mediated by donor T cells in response to alloantigen presented by major histocompatibility complex (MHC) class I and MHC class II on antigen-presenting cells (APCs). The role of the microbiota in altering the severity of GVHD has been noted. Intensive anti-biotic-mediated gut decontamination attenuates acute GVHD and improves survival in clinical settings, including phase III randomized studies. However, qualitative changes in the microbiota, particularly the loss of microbiota diversity characterized by depletion of short-chain fatty acid-producing anaerobes, have been associated with impaired transplant outcome indicating that distinct protective and pathogenic components of the microbiota affect GVHD and survival following BMT. In this paper, that authors found that (1) under homeostatic conditions,IL-12 secretion from macrophages induced IFNg secretion by lamina proprialymphocytes in a microbiota and MyD88/TRIF-dependent manner, resulting in MHC class II expression by IECs in the ileum, and (2) MHC class II-expressing IECsfunctioned as APCs to prime donor CD4+ T cells in vivo and induced lethal acute GVHD. Furthermore, conditioning with TBI invoked additional IL-12 secretion by macrophages in a microbiota- dependent manner and rapid IFNg secretion by conventional T cells in the GI tract, which resulted in rapid and marked enhancement of MHC class II expression, together with CD80 expression by IECs. Furthermore, IEC-specific deletion of MHC class II abrogated gut pathology and lethal GVHD. Abrogation of GVHD lethality was also achieved by preventing MHC class IIexpression on IECs via IL-12/23p40 neutralization pre- transplant.
/10.1016/j.immuni..08.011
02
Regulatory T cells in skin are uniquely poised to suppress profibrotic immune responses
Lokesh A. Kalekar,Jarish N. Cohen, Nicolas, et al.
Sci. Immunol,
Fibroblast activation is a key event in tissue remodeling after injury. It is becoming increasingly evident that the immune system plays a major role in the activation of quiescent fibroblasts to ECM-producing myofibroblasts. Effector T cell (Teff) production of the T helper 2 (TH2) cytokines,interleukin-4 (IL-4) and IL-13, drives fibroblast activation via signaling through their cognate receptors expressed on fibroblasts and/or on tissue myeloid cells, resulting in increased ECM deposition. Tregs have been shown to secrete the profibrotic cytokine TGF-β; however, these cells are also capable of suppressing the production of profibrogenic cytokines, such as IL-4 and IL-13. It has been shown previously that Tregs in skin and adipose tissue adopt a “TH2 phenotype,” which is identified by the expression of Il1rl1 (ST2; IL-33 receptor) and Areg. In this paper, the authors indicated that although most Tregs in skin express Gata3, Areg and Il1rl1 are preferentially expressed on specific subsets. This expression pattern is quite different than that observed in lung-resident Tregs.Furthermore, skin Tregs do express relatively high levels of several TGF-β receptors suggesting that skin-resident Tregs could function as “TGF-βsinks,” acting to sequester this cytokine. Both acute depletion and chronic reduction of Tregs resulted in spontaneous skin fibroblast activation, profibrotic gene expression, and dermal fibrosis, all of which were exacerbated in a bleomycin-induced murine model of skin sclerosis. Lineage-specific deletion of Gata3 in Tregs resulted in an exacerbation of TH2 cytokine secretion that was preferential to skin, resulting in enhanced fibroblast activation and dermal fibrosis.
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