Cell Reports (Mar 2021)

Liver-specific T regulatory type-1 cells program local neutrophils to suppress hepatic autoimmunity via CRAMP

  • Channakeshava Sokke Umeshappa,
  • Patricia Solé,
  • Bas G.J. Surewaard,
  • Jun Yamanouchi,
  • Saswat Mohapatra,
  • Muhammad Myn Uddin,
  • Robert Clarke,
  • Mireia Ortega,
  • Santiswarup Singha,
  • Debajyoti Mondal,
  • Yang Yang,
  • Dario A.A. Vignali,
  • Pau Serra,
  • Paul Kubes,
  • Pere Santamaria

Journal volume & issue
Vol. 34, no. 13
p. 108919

Abstract

Read online

Summary: Neutrophils with immunoregulatory properties, also referred to as type-2 neutrophils (N2), myeloid-derived suppressor cells (MDSCs), or tumor-associated neutrophils (TANs), comprise a heterogeneous subset of cells that arise from unknown precursors in response to poorly understood cues. Here, we find that, in several models of liver autoimmunity, pharmacologically induced, autoantigen-specific T regulatory type-1 (TR1) cells and TR1-cell-induced B regulatory (Breg) cells use five immunoregulatory cytokines to coordinately recruit neutrophils into the liver and program their transcriptome to generate regulatory neutrophils. The liver-associated neutrophils from the treated mice, unlike their circulating counterparts or the liver neutrophils of sick mice lacking antigen-specific TR1 cells, are proliferative, can transfer disease protection to immunocompromised hosts engrafted with pathogenic effectors, and blunt antigen-presentation and local autoimmune responses via cathelin-related anti-microbial peptide (CRAMP), a cathelicidin, in a CRAMP-receptor-dependent manner. These results, thus, identify antigen-specific regulatory T cells as drivers of tissue-restricted regulatory neutrophil formation and CRAMP as an effector of regulatory neutrophil-mediated immunoregulation.

Keywords