Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells

Blood. 2016 Apr 14;127(15):1930-9. doi: 10.1182/blood-2015-09-672428. Epub 2016 Feb 2.

Abstract

Caveolin-1 (Cav-1) is a key organizer of membrane specializations and a scaffold protein that regulates signaling in multiple cell types. We found increased Cav-1 expression in human and murine T cells after allogeneic hematopoietic cell transplantation. Indeed, Cav-1(-/-)donor T cells caused less severe acute graft-versus-host disease (GVHD) and yielded higher numbers of regulatory T cells (Tregs) compared with controls. Depletion of Tregs from the graft abrogated this protective effect. Correspondingly, Treg frequencies increased when Cav-1(-/-)T cells were exposed to transforming growth factor-β/T-cell receptor (TCR)/CD28 activation or alloantigen stimulation in vitro compared with wild-type T cells. Mechanistically, we found that the phosphorylation of Cav-1 is dispensable for the control of T-cell fate by using a nonphosphorylatable Cav-1 (Y14F/Y14F) point-mutation variant. Moreover, the close proximity of lymphocyte-specific protein tyrosine kinase (Lck) to the TCR induced by TCR-activation was reduced in Cav-1(-/-)T cells. Therefore, less TCR/Lck clustering results in suboptimal activation of the downstream signaling events, which correlates with the preferential development into a Treg phenotype. Overall, we report a novel role for Cav-1 in TCR/Lck spatial distribution upon TCR triggering, which controls T-cell fate toward a regulatory phenotype. This alteration translated into a significant increase in the frequency of Tregs and reduced GVHD in vivo.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • CD28 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / cytology
  • Caveolin 1 / genetics
  • Caveolin 1 / metabolism*
  • Caveolin 1 / physiology*
  • Cell Differentiation
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation*
  • Graft vs Host Disease / immunology
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Phosphorylation
  • Prospective Studies
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction
  • T-Lymphocytes / cytology*
  • T-Lymphocytes, Regulatory / cytology
  • Transforming Growth Factor beta / metabolism
  • Transplantation, Homologous

Substances

  • Adaptor Proteins, Signal Transducing
  • CAV1 protein, human
  • CD28 Antigens
  • Cav1 protein, mouse
  • Caveolin 1
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Receptors, Antigen, T-Cell
  • Sh2d2a protein, mouse
  • Transforming Growth Factor beta