γδ T Cell-Secreted XCL1 Mediates Anti-CD3-Induced Oral Tolerance

Published on Nov 15, 2019in Journal of Immunology5.422
· DOI :10.4049/JIMMUNOL.1900784
Rafael M. Rezende19
Estimated H-index: 19
(Brigham and Women's Hospital),
Brenda Naemi Nakagaki8
Estimated H-index: 8
(UFMG: Universidade Federal de Minas Gerais)
+ 9 AuthorsHoward L. Weiner167
Estimated H-index: 167
Sources
Abstract
: Oral tolerance is defined as the specific suppression of cellular and/or humoral immune responses to an Ag by prior administration of the Ag through the oral route. Although the investigation of oral tolerance has classically involved Ag feeding, we have found that oral administration of anti-CD3 mAb induced tolerance through regulatory T (Treg) cell generation. However, the mechanisms underlying this effect remain unknown. In this study, we show that conventional but not plasmacytoid dendritic cells (DCs) are required for anti-CD3-induced oral tolerance. Moreover, oral anti-CD3 promotes XCL1 secretion by small intestine lamina propria γδ T cells that, in turn, induces tolerogenic XCR1+ DC migration to the mesenteric lymph node, where Treg cells are induced and oral tolerance is established. Consistent with this, TCRδ-/- mice did not develop oral tolerance upon oral administration of anti-CD3. However, XCL1 was not required for oral tolerance induced by fed Ags, indicating that a different mechanism underlies this effect. Accordingly, oral administration of anti-CD3 enhanced oral tolerance induced by fed MOG35-55 peptide, resulting in less severe experimental autoimmune encephalomyelitis, which was associated with decreased inflammatory immune cell infiltration in the CNS and increased Treg cells in the spleen. Thus, Treg cell induction by oral anti-CD3 is a consequence of the cross-talk between γδ T cells and tolerogenic DCs in the gut. Furthermore, anti-CD3 may serve as an adjuvant to enhance oral tolerance to fed Ags.
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: The immune system plays a role in the pathogenesis of non-alcoholic steatohepatitis (NASH) underlying hepatocyte injury and fibrosis progression at all disease stages. Oral administration of anti-CD3 monoclonal antibody (mAb) has been shown in preclinical studies to be an effective method for systemic immune modulation and alleviates immune-mediated disorders without T cell depletion. In the present review, we summarize the concept of the oral administration of humanized anti-CD3 mAb in patien...
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#1Rafael M. Rezende (Brigham and Women's Hospital)H-Index: 19
#2Howard L. Weiner (Brigham and Women's Hospital)H-Index: 167
: Oral tolerance can be defined as an inhibition of specific immune responsiveness to subsequent parenteral injections of proteins to which an individual or animal has been previously exposed via the oral route. Multiple mechanisms of tolerance are induced by oral-fed antigens, but induction of regulatory CD4 T-cells expressing the transcription factor Foxp3 and the membrane-bound TGF-β stands out as the major players in oral tolerance. Oral antigen administration suppresses several animal model...
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#1Rafael M. Rezende (Brigham and Women's Hospital)H-Index: 19
#2Howard L. Weiner (Brigham and Women's Hospital)H-Index: 167
Abstract Since its first description by Wells and Osbourne in 1911, oral tolerance has intrigued researchers due to its potential for therapeutic applications. Oral tolerance can be defined as an inhibition of specific immune responsiveness to subsequent parenteral injections of proteins to which an individual or animal has been previously exposed via the oral route. Tolerance induction to commensal bacteria and dietary proteins represents the major immunological event taking place in the gut in...
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#1Chantal Kuhn (Brigham and Women's Hospital)H-Index: 15
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The induction of tolerance is a major goal of immunotherapy. Investigations over the last 20 years have shown that anti-CD3 monoclonal antibodies (mAbs) effectively treat autoimmune disease in animal models and have also shown promise in clinical trials. Tolerance induction by anti-CD3 mAbs is related to the induction of Tregs that control pathogenic autoimmune responses. Here, we review preclinical and clinical studies in which intravenous or mucosal administration of anti-CD3 mAbs has been emp...
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The subsets of antigen presenting cells (APCs) that mediate tolerance to oral antigens remain unclear. Mucida and colleagues use lineage-specific depletion of APCs to show that monocyte-derived APCs are dispensable, while classical dendritic cells are critical, for the induction of regulatory T cells and oral tolerance.
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