CD47(low) status on CD4 effectors is necessary for the contraction/resolution of the immune response in humans and mice

PLoS One. 2012;7(8):e41972. doi: 10.1371/journal.pone.0041972. Epub 2012 Aug 1.

Abstract

How do effector CD4 T cells escape cell death during the contraction of the immune response (IR) remain largely unknown. CD47, through interactions with thrombospondin-1 (TSP-1) and SIRP-α, is implicated in cell death and phagocytosis of malignant cells. Here, we reported a reduction in SIRP-α-Fc binding to effector memory T cells (T(EM)) and in vitro TCR-activated human CD4 T cells that was linked to TSP-1/CD47-induced cell death. The reduced SIRP-α-Fc binding (CD47(low) status) was not detected when CD4 T cells were stained with two anti-CD47 mAbs, which recognize distinct epitopes. In contrast, increased SIRP-α-Fc binding (CD47(high) status) marked central memory T cells (T(CM)) as well as activated CD4 T cells exposed to IL-2, and correlated with resistance to TSP-1/CD47-mediated killing. Auto-aggressive CD4 effectors, which accumulated in lymph nodes and at mucosal sites of patients with Crohn's disease, displayed a CD47(high) status despite a high level of TSP-1 release in colonic tissues. In mice, CD47 (CD47(low) status) was required on antigen (Ag)-specific CD4 effectors for the contraction of the IR in vivo, as significantly lower numbers of Ag-specific CD47(+/+)CD4 T cells were recovered when compared to Ag-specific CD47(-/-) CD4 T cells. In conclusion, we demonstrate that a transient change in the status of CD47, i.e. from CD47(high) to CD47(low), on CD4 effectors regulates the decision-making process that leads to CD47-mediated cell death and contraction of the IR while maintenance of a CD47(high) status on tissue-destructive CD4 effectors prevents the resolution of the inflammatory response.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • CD47 Antigen / genetics
  • CD47 Antigen / immunology*
  • Cell Death / genetics
  • Clonal Deletion*
  • Crohn Disease / genetics
  • Crohn Disease / immunology
  • Crohn Disease / pathology
  • Female
  • Humans
  • Immunologic Memory*
  • Interleukin-2 / genetics
  • Interleukin-2 / immunology
  • Male
  • Mice
  • Mice, Knockout
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology

Substances

  • Antigens, Differentiation
  • CD47 Antigen
  • CD47 protein, human
  • Cd47 protein, mouse
  • IL2 protein, human
  • Interleukin-2
  • Ptpns1 protein, mouse
  • Receptors, Immunologic
  • SIRPA protein, human