CD45 regulates GM-CSF, retinoic acid and T-cell homing in intestinal inflammation

Mucosal Immunol. 2016 Nov;9(6):1514-1527. doi: 10.1038/mi.2016.23. Epub 2016 Mar 23.

Abstract

CD45 is a leukocyte-specific tyrosine phosphatase important for T-cell development, and as a result, CD45-/- mice have substantially reduced numbers of T cells. Here we show that, upon dextran sodium sulfate (DSS)-induced colitis, CD45-/- mice have equivalent intestinal pathology and T-cell numbers in their colon as C57BL/6 mice and show enhanced weight loss. CD45-/- mice have a greater percentage of α4β7+ T cells prior to and after colitis and an increased percentage of T cells producing inflammatory cytokines in the inflamed colon, suggesting that CD45-/- effector T cells preferentially home to the intestine. In DSS-induced colitis in CD45RAG-/- mice lacking an adaptive immune system, CD45 was required for optimal granulocyte-macrophage colony-stimulating factor (GM-CSF) and retinoic acid (RA) production by innate immune cells. Addition of CD45+/+ T cells led to greater weight loss in the RAG-/- mice compared with CD45RAG-/- mice that correlated with reduced α4β7+ T cells and lower recruitment to the colon of CD45RAG-/- mice in DSS-induced colitis. Addition of exogenous GM-CSF to CD45RAG-/- mice rescued RA production, increased colonic T-cell numbers, and increased weight loss. This demonstrates opposing effects of CD45 in innate and adaptive immune cells in proinflammatory responses and the expression of the gut-homing molecule, α4β7.

MeSH terms

  • Animals
  • Antigens, Ly / metabolism
  • Cell Movement / genetics
  • Cell Movement / immunology
  • Colitis / chemically induced
  • Colitis / genetics
  • Colitis / immunology
  • Colitis / metabolism
  • Cytokines / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dextran Sulfate / adverse effects
  • Disease Models, Animal
  • Gene Expression
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Immunity, Innate
  • Inflammation / immunology
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Inflammation Mediators / metabolism
  • Intestinal Mucosa / metabolism*
  • Intestines / immunology
  • Intestines / pathology
  • Leukocyte Common Antigens / genetics
  • Leukocyte Common Antigens / metabolism*
  • Lymph Nodes / immunology
  • Lymph Nodes / metabolism
  • Mice
  • Mice, Knockout
  • NK Cell Lectin-Like Receptor Subfamily B / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Tretinoin / metabolism*

Substances

  • Antigens, Ly
  • Cytokines
  • Inflammation Mediators
  • Klrb1c protein, mouse
  • NK Cell Lectin-Like Receptor Subfamily B
  • Tretinoin
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Dextran Sulfate
  • Leukocyte Common Antigens

Grant support