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• W4289444329 abstract "See “A small CEACAM5 peptide restores the protective function of CD8+ regulatory T cells in Crohn's disease,” by Dunkin D, Merlino F, Correale C, et al, on page 1090. See “A small CEACAM5 peptide restores the protective function of CD8+ regulatory T cells in Crohn's disease,” by Dunkin D, Merlino F, Correale C, et al, on page 1090. Regulatory T cells are key players in the maintenance of intestinal homeostasis. A defect or a lack of activation of regulatory T cells can lead to mucosal inflammation. Many subsets of T cells with a regulatory function are present in the intestinal mucosa.1Allez M. Mayer L. Regulatory T cells: peace keepers in the gut.Inflamm Bowel Dis. 2004; 10: 666-676Crossref PubMed Scopus (105) Google Scholar Yio and Mayer2Yio X.Y. Mayer L. Characterization of a 180-kDa intestinal epithelial cell membrane glycoprotein, gp180. A candidate molecule mediating t cell-epithelial cell interactions.J Biol Chem. 1997; 272: 12786-12792Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar explored during his career the role of intestinal epithelial cells (IEC) in regulating mucosal immune responses. He and his group identified a molecule expressed on normal IEC that appears to play a role in the activation of antigen nonspecific CD8+ suppressor T cells.2Yio X.Y. Mayer L. Characterization of a 180-kDa intestinal epithelial cell membrane glycoprotein, gp180. A candidate molecule mediating t cell-epithelial cell interactions.J Biol Chem. 1997; 272: 12786-12792Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar This molecule, called initially gp180 (180-kD glycoprotein) and later identified as CEACAM5, mediated binding to CD8 and resulted in the activation of tyrosine kinase p56lck.3Li Y. Yio X.Y. Mayer L. Human intestinal epithelial cell-induced CD8+ T cell activation is mediated through CD8 and the activation of CD8-associated p56lck.J Exp Med. 1995; 182: 1079-1088Crossref PubMed Scopus (73) Google Scholar, 4Campbell N.A. Park M.S. Toy L.S. et al.A non-class I MHC intestinal epithelial surface glycoprotein, gp180, binds to CD8.Clin Immunol. 2002; 102: 267-274Crossref PubMed Scopus (25) Google Scholar, 5Roda G. Jianyu X. Park M.S. et al.Characterizing CEACAM5 interaction with CD8α and CD1d in intestinal homeostasis.Mucosal Immunol. 2014; 7: 615-624Crossref PubMed Scopus (18) Google Scholar IECs isolated from normal individuals are able to activate a subset of CD8+ with regulatory function, through a complex formed by gp180/CEACAM5 and CD1d.6Allez M. Brimnes J. Dotan I. et al.Expansion of CD8+ T cells with regulatory function after interaction with intestinal epithelial cells.Gastroenterology. 2002; 123: 1516-1526Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar,7Allez M. Brimnes J. Shao L. et al.Activation of a unique population of CD8(+) T cells by intestinal epithelial cells.Ann N Y Acad Sci. 2004; 1029: 22-35Crossref PubMed Scopus (28) Google Scholar CEACAM5 interacts with the CD8 alpha chain through its N-domain and with CD1d through its B3 domain.5Roda G. Jianyu X. Park M.S. et al.Characterizing CEACAM5 interaction with CD8α and CD1d in intestinal homeostasis.Mucosal Immunol. 2014; 7: 615-624Crossref PubMed Scopus (18) Google Scholar The expression of gp180/CEACAM5 seemed to be defective in inflammatory bowel disease (IBD).8Toy L.S. Yio X.Y. Lin A. et al.Defective expression of gp180, a novel CD8 ligand on intestinal epithelial cells, in inflammatory bowel disease.J Clin Invest. 1997; 100: 2062-2071Crossref PubMed Scopus (75) Google Scholar,9Roda G. Dahan S. Mezzanotte L. et al.Defect in CEACAM family member expression in Crohn's disease IECs is regulated by the transcription factor SOX9.Inflamm Bowel Dis. 2009; 15: 1775-1783Crossref PubMed Scopus (28) Google Scholar Thus, the ability of gp180/CEACAM5 to interact with T cells is decreased in IBD. Accordingly, CD8+ T cells with regulatory activity are present in the lamina propria of normal healthy individuals, but not in patients with IBD.10Brimnes J. Allez M. Dotan I. et al.Defects in CD8+ regulatory T cells in the lamina propria of patients with inflammatory bowel disease.J Immunol. 2005; 174: 5814-5822Crossref PubMed Scopus (161) Google Scholar It was also shown that mucosal suppressive T cell-lines obtained from patients with Crohn’s disease (CD) have a decrease ability to suppress the proliferation of CD4+ T cells compared with lines obtained from controls.11Rabinowitz K.M. Wang Y. Chen E.Y. et al.Transforming growth factor β signaling controls activities of human intestinal CD8(+)T suppressor cells.Gastroenterology. 2013; 144: 601-612.e1Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar In fact, IECs from patients with IBD rather activate CD4+ T cells to proliferate and produce interferon-γ.12Dotan I. Allez M. Nakazawa A. et al.Intestinal epithelial cells from inflammatory bowel disease patients preferentially stimulate CD4+ T cells to proliferate and secrete interferon-gamma.Am J Physiol Gastrointest Liver Physiol. 2007; 292: G1630-G1640Crossref PubMed Scopus (65) Google Scholar Indeed, IECs in IBD overexpress several class Ib molecules such as MICA/B and ULBPs, which may contribute to the activation of effector T cells with proinflammatory and cytotoxic properties.13Allez M. Tieng V. Nakazawa A. et al.CD4+NKG2D+ T cells in Crohn's disease mediate inflammatory and cytotoxic responses through MICA interactions.Gastroenterology. 2007; 132: 2346-2358Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar,14Pariente B. Mocan I. Camus M. et al.Activation of the receptor NKG2D leads to production of Th17 cytokines in CD4+ T cells of patients with Crohn's disease.Gastroenterology. 2011; 141: 217-226.e1-e2Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar A treatment restoring the balanced activity between effector and regulatory mechanisms could highly benefit patients with IBD. In this issue of Gastroenterology, Dunkin et al15Dunkin D. Merlino F. Correale C. et al.A small CEACAM5 peptide restores the protective function of CD8+ regulatory T cells in Crohn's disease.Gastroenterology. 2022; 163: 1090-1093Abstract Full Text Full Text PDF Scopus (1) Google Scholar report on the identification of small peptides isolated from CEACAM5. The authors identified a peptide of 12 amino acids able to activate in vitro CD8+ T cells isolated from peripheral blood and the intestinal mucosa. They demonstrate that this peptide is able to restore the regulatory function of CD8+ T cells isolated from the lamina propria of patients with CD. These data suggest that CEACAM5 peptides could modulate the uncontrolled inflammation of CD. In their article, the authors first demonstrated that CEACAM5 can change the function of CD8+ T cells isolated from the lamina propria of patients. Indeed, LP CD8+ T cells preincubated with CEACAM5 became suppressive in contrast with those not preincubated with CEACAM5 (Figure 1C). Interestingly, culture of PB CD8+ T cells with CEACAM5 induced an increased production of IL-10. They designed an N-domain CEACAM5 overlapping peptide library to precisely identify a minimal length CEACAM5-derived peptide that would mimic the full-length CEACAM5 protein activity on CD8+ T cells. They found a 12 amino-acid peptide (Pep12) able to induce a regulatory activity even in CD8+ lamina propria T cells from patients with CD as well as seen for full-length CEACAM5. Three shorter derivatives of Pep12 were found to possess the strongest suppressive function. Thus, CEACAM5 seems to be a potent modifier of intestinal T-cell function. Its epithelial origin points to the importance of the IEC as a major participant in mucosal immune responses. The abnormal expression of diverse receptors at the basolateral surface of IECs in IBD may not only contribute to a lack of activation of regulatory subsets as shown in this study, but also to the increased activation of effector T-cell subsets with proinflammatory properties (Figure 1). Furthermore, the finding of a small peptide able to restore CD8+ regulatory activity in the intestinal mucosa of patients with IBD could provide a new therapeutic avenue in IBD (Figure 1B). The suppressive mechanism of these CD8+ T cells could be mediated by IL-10. Previous studies suggested that CD8+ regulatory T cells activated by IECs through the gp180/CEACAM5 need a cell contact to have an effect on their target, but local suppressive cytokines such as IL-10 and transforming growth factor-β could be involved.6Allez M. Brimnes J. Dotan I. et al.Expansion of CD8+ T cells with regulatory function after interaction with intestinal epithelial cells.Gastroenterology. 2002; 123: 1516-1526Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar,11Rabinowitz K.M. Wang Y. Chen E.Y. et al.Transforming growth factor β signaling controls activities of human intestinal CD8(+)T suppressor cells.Gastroenterology. 2013; 144: 601-612.e1Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Importantly, the ex vivo activation of CD8+-suppressive T cells through CEACAM5 and the identified peptides is independent of T-cell receptor signaling. CEACAM5 forms a complex with CD1d on the basolateral surface of IECs, and previous data suggest that CD8+ regulatory T cells activated by IECs interact with this complex formed by CEACAM5 and CD1d.5Roda G. Jianyu X. Park M.S. et al.Characterizing CEACAM5 interaction with CD8α and CD1d in intestinal homeostasis.Mucosal Immunol. 2014; 7: 615-624Crossref PubMed Scopus (18) Google Scholar Antigens can be processed and presented on MHC molecules by IECs, and CD1d can present antigens at the surface of IECs.16van de Wal Y. Corazza N. Allez M. et al.Delineation of a CD1d-restricted antigen presentation pathway associated with human and mouse intestinal epithelial cells.Gastroenterology. 2003; 124: 1420-1431Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Early data suggested that those CD8+ T cells activated by IECs through the complex formed by CD1d and CEACAM5 have a restricted repertoire.7Allez M. Brimnes J. Shao L. et al.Activation of a unique population of CD8(+) T cells by intestinal epithelial cells.Ann N Y Acad Sci. 2004; 1029: 22-35Crossref PubMed Scopus (28) Google Scholar In future studies, it would be of interest to further explore the T-cell receptor specificity of these CD8+ regulatory T activated by IECs. As discussed by Dunkin et al,15Dunkin D. Merlino F. Correale C. et al.A small CEACAM5 peptide restores the protective function of CD8+ regulatory T cells in Crohn's disease.Gastroenterology. 2022; 163: 1090-1093Abstract Full Text Full Text PDF Scopus (1) Google Scholar a clinical use of these small peptides will represent a challenge. Indeed, a number of modification of the peptides will be needed to obtain a local delivery of these peptides in the intestinal mucosa.15Dunkin D. Merlino F. Correale C. et al.A small CEACAM5 peptide restores the protective function of CD8+ regulatory T cells in Crohn's disease.Gastroenterology. 2022; 163: 1090-1093Abstract Full Text Full Text PDF Scopus (1) Google Scholar These oral drugs would have the benefit of a local delivery without systemic effect and represent an elegant manner to maintain the physiological homeostatic balance, even if it remains to be demonstrated that the functional restoration of CD8+ regulatory T cells will be sufficient for the induction or maintenance of mucosal healing in CD. A Small CEACAM5 Peptide Restores the Protective Function of CD8+ Regulatory T Cells in Crohn’s DiseaseGastroenterologyVol. 163Issue 4PreviewIntestinal epithelial cells (IECs) play a pivotal role in controlling immune responses by activation of suppressive CD8+ T regulatory (Treg) cells.1,2 Indeed, we have shown that at homeostasis, IECs interact with CD8+ T cells through a complex formed by CEACAM5 and CD1d on IECs and CD8α and T-cell receptor (TCR) on CD8+ T cells.2 CEACAM5 interacts with CD8α through its N-domain, and it is the only CEACAM family member that interacts with CD1d through its B3-domain.1 This unique set of interactions facilitates antigen presentation by CD1d to T cells, allowing the subsequent activation of CD8+ Treg cells, which possess a potent function in suppressing effector T cell responses and hence are essential to prevent autoimmune disorders. Full-Text PDF" @default.
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• W4289444329 title "A CEACAM5-derived Peptide Activating CD8+ Regulatory T Cells: A Future Option for Restoring Mucosal Homeostasis in Crohn’s Disease?" @default.
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