Fever Promotes T Lymphocyte Trafficking via a Thermal Sensory Pathway Involving Heat Shock Protein 90 and α4 Integrins

Immunity. 2019 Jan 15;50(1):137-151.e6. doi: 10.1016/j.immuni.2018.11.013.


Fever is an evolutionarily conserved response that confers survival benefits during infection. However, the underlying mechanism remains obscure. Here, we report that fever promoted T lymphocyte trafficking through heat shock protein 90 (Hsp90)-induced α4 integrin activation and signaling in T cells. By inducing selective binding of Hsp90 to α4 integrins, but not β2 integrins, fever increased α4-integrin-mediated T cell adhesion and transmigration. Mechanistically, Hsp90 bound to the α4 tail and activated α4 integrins via inside-out signaling. Moreover, the N and C termini of one Hsp90 molecule simultaneously bound to two α4 tails, leading to dimerization and clustering of α4 integrins on the cell membrane and subsequent activation of the FAK-RhoA pathway. Abolishment of Hsp90-α4 interaction inhibited fever-induced T cell trafficking to draining lymph nodes and impaired the clearance of bacterial infection. Our findings identify the Hsp90-α4-integrin axis as a thermal sensory pathway that promotes T lymphocyte trafficking and enhances immune surveillance during infection.

Keywords: Hsp90; fever; lymphocyte trafficking; thermal stress; α4 integrins.

Publication types

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

MeSH terms

  • Animals
  • Bacterial Load
  • Cell Adhesion
  • Cell Movement
  • Dimerization
  • Fever / immunology*
  • Focal Adhesion Kinase 1 / metabolism
  • HSP90 Heat-Shock Proteins / metabolism*
  • Immunologic Surveillance
  • Integrin alpha4 / genetics
  • Integrin alpha4 / metabolism*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Binding
  • Salmonella Infections / immunology*
  • Salmonella typhimurium / immunology*
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • rhoA GTP-Binding Protein / metabolism


  • HSP90 Heat-Shock Proteins
  • Integrin alpha4
  • Focal Adhesion Kinase 1
  • Ptk2 protein, mouse
  • rhoA GTP-Binding Protein