Circulating integrin alpha4/beta7+ lymphocytes targeted by vedolizumab have a pro-inflammatory phenotype

Clin Immunol. 2018 Aug:193:24-32. doi: 10.1016/j.clim.2018.05.006. Epub 2018 May 26.

Abstract

Integrin alpha4/beta7 on circulating lymphocytes identifies them as gut-tropic, and can be targeted by the humanized antibody vedolizumab to treat inflammatory bowel disease (IBD). We found lymphocytes expressing alpha4/beta7 were significantly more responsive to the pro-inflammatory cytokines IL-6, IL-7, and IL-21, and less responsive to the regulatory T cell (Treg)-supporting cytokine IL-2. Alpha4/beta7 was expressed by a smaller percent of FOXP3 + Helios+ thymically-derived Tregs (tTregs) than FOXP3 + Helios- peripherally-derived Tregs (pTregs) or FOXP3- effector T cells. Integrin alpha4/beta7+ CD4 T cells were also rare among cells expressing the Th2 marker CRTh2, but enriched in cells bearing the circulating T follicular helper cell marker CXCR5. Thus the effect of this anti-integrin therapy on the mucosal immune system may be more qualitative than quantitative, and selectively replace pro-inflammatory effector cells with Tregs and Th2 cells to facilitate immune tolerance in the mucosa without globally depleting lymphocytes from the intestinal mucosa.

Keywords: Crohn's disease; FOXP3; Helios; IL-2, IL-6, IL-7, IL-21; Integrin; Stat; Th1; Th2; Treg; Vedolizumab; cT(FH).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Blood Circulation
  • Cytokines / metabolism
  • Female
  • Forkhead Transcription Factors / metabolism
  • Gastrointestinal Agents / therapeutic use*
  • Humans
  • Ikaros Transcription Factor / metabolism
  • Immune Tolerance
  • Inflammation Mediators / metabolism
  • Inflammatory Bowel Diseases / drug therapy
  • Inflammatory Bowel Diseases / immunology*
  • Integrins / immunology
  • Integrins / metabolism*
  • Intestines / immunology*
  • Male
  • Middle Aged
  • Receptors, CXCR5 / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • Th1 Cells / immunology*
  • Th2 Cells / immunology*

Substances

  • Antibodies, Monoclonal, Humanized
  • CXCR5 protein, human
  • Cytokines
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Gastrointestinal Agents
  • IKZF2 protein, human
  • Inflammation Mediators
  • Integrins
  • Receptors, CXCR5
  • integrin alpha4beta7
  • Ikaros Transcription Factor
  • vedolizumab