According to a study published in the journal Immunity, fever alters surface proteins on immune cells to make them better able to travel via blood vessels to reach the site of infection.
Fever is an evolutionarily conserved response in both endothermic and ectothermic species and confers survival benefits during infection and injury. Lin et al identify that the Hsp90-a4-integrin axis serves as a thermal sensory pathway that responds to fever to promote T cell trafficking and enhance immune surveillance during infection. Image credit: Lin et al, doi: 10.1016/j.immuni.2018.11.013.
To get to an infection, lymphocytes need to adhere to the blood vessel and then transmigrate into the infected tissue or lymph node.
During this step, cell adhesion molecules known as integrins are expressed on the surface of lymphocytes. These molecules control lymphocyte trafficking during inflammation.
“One good thing about fever is that it can promote lymphocyte trafficking to the site of infection, so you will have more immune cells in the infected region that will get rid of the pathogen,” said study senior author Professor JianFeng Chen, a researcher at the Shanghai Institute of Biochemistry and Cell Biology, China.
Professor Chen and co-authors discovered that fever increases the expression of heat shock protein 90 (Hsp 90) in T lymphocytes.
Hsp 90 binds to a type of integrin on the lymphocytes — α4 integrins — which promote lymphocyte adhesion to the blood vessel and ultimately to expedited migration to the site of infection.
The team found that fever-induced Hsp90 binds to the integrin tail and induces integrin activation.
Moreover, one Hsp90 can bind to two integrins leading to a clustering of integrins on the lymphocyte surface.
As a result, the clustered integrins activate a signaling pathway that promotes lymphocyte transmigration.
“Our findings show that this mechanism not only applies to lymphocytes but also to innate immune cells like monocytes,” Professor Chen said.
“It is a general mechanism that can apply to lots of different immune cells expressing α4 integrins.”
The scientists also used mice in studies of bacterial infection and other fever models to confirm their findings.
“We found Hsp90 can only be induced at a temperature above 38.5 degrees Celsius (101.3 degrees Fahrenheit). The mechanism is targeted and effective, yet reversible,” Professor Chen said.
The researchers also believe other stresses, not just fever, can induce Hsp90 expression.
“That’s why we think that in different situations, such as autoimmune disease and cancer, this Hsp90-α4 integrin pathway may be involved,” Professor Chen said.
“In autoimmune disease, aberrant trafficking of immune cells to different organs or tissues may lead to disease.”
“But if you block this pathway, you can maybe inhibit the trafficking of the immune cells during chronic inflammation or in autoimmune diseases.”
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ChangDong Lin et al. 2019. Fever Promotes T Lymphocyte Trafficking via a Thermal Sensory Pathway Involving Heat Shock Protein 90 and α4 Integrins. Immunity 50 (1): 137-151; doi: 10.1016/j.immuni.2018.11.013
