Rapp et al. demonstrate that high levels of CCL22 are constitutively expressed by DCs, particularly CD103+ DCs, in the lymph node, and that CCL22 induces DC contact with Tregs via their cognate CCR4 receptor. This contact is required for Treg-mediated suppression of adaptive immunity, as indicated by the significantly increased T cell responses in OVA-vaccinated CCL22-/- mice and in WT mice vaccinated with OVA-pulsed CCL2-/- DCs. OVA vaccination decreased OVA-expressing tumor growth and increased survival in CCL22-/- mice. In a separate model, CCL22 deficiency rendered mice more susceptible to colitis.
Chemokines have crucial roles in organ development and orchestration of leukocyte migration. The chemokine CCL22 is expressed constitutively at high levels in the lymph node, but the functional significance of this expression is so far unknown. Studying a newly established CCL22-deficient mouse, we demonstrate that CCL22 expression by dendritic cells (DCs) promotes the formation of cell-cell contacts and interaction with regulatory T cells (T reg) through their CCR4 receptor. Vaccination of CCL22-deficient mice led to excessive T cell responses that were also observed when wild-type mice were vaccinated using CCL22-deficient DCs. Tumor-bearing mice with CCL22 deficiency showed prolonged survival upon vaccination, and further, CCL22-deficient mice had increased susceptibility to inflammatory disease. In conclusion, we identify the CCL22-CCR4 axis as an immune checkpoint that is crucial for the control of T cell immunity.
Author Info: (1) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. (2) Center of Inte
Author Info: (1) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. (2) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. (3) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. (4) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. (5) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. (6) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. (7) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. (8) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. (9) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. (10) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. (11) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. (12) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. (13) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. (14) Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany. (15) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. (16) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. (17) Department of Immunology, Harvard Medical School, Boston, MA. (18) School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland. Department of Anaesthetics, Pharmacology, Intensive Care and Emergencies, Faculty of Medicine, University of Geneva, Geneva, Switzerland. (19) Department of Immunology, Harvard Medical School, Boston, MA uva@hms.harvard.edu. The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston, MA. (20) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany endres@lmu.de. German Cancer Consortium (DKTK), partner site Munich, Munich, Germany. (21) Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. Department of Medicine II, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany.
