Research Reveals Inner Workings of Immune System ¡§Thermostat¡¨

When bacteria, viruses or parasites attack, immune system cells unleash the soldiers. These ¡§hot¡¨ protein compounds kill invaders ¡V but also trigger inflammation, which, if unchecked, can destroy tissue, induce shock and kill the host. So immune system cells let loose another protein compound to cool down the immune response.

Precisely how this immune system ¡§thermostat¡¨ operates is unclear. The leading hypothesis is that these compounds ¡V which act as furnace and air conditioner ¡V battle it out over control of the system¡¦s inflammatory response.

But new research, led by George Yap of Brown University, shows that these cytokines don¡¦t operate independently and in opposition. They operate in harmony and are controlled by the same master. In work published in the Journal of Immunology, Yap and his team show that the ¡§cool¡¨ anti-inflammatory protein compound known as Interleukin 10 is activated by Interferon-£^, a class of proteins secreted by a class of white blood cells known as T helper 1 cells. The team then traced secretion of Interferon-£^ indirectly to tyrosine kinase 2, or tyk2, the same protein that signals ¡§hot¡¨ inflammatory cytokines Interleukin 12 and Interferon-£ and Interferon-£].

¡§Under the prevailing paradigm, scientists believe that the pro- and anti-inflammatory arms of the immune system just antagonize each other,¡¨ Yap said. ¡§Here we show that they actually induce each other. ¡¥Hot¡¦ cytokines don¡¦t inhibit ¡¥cool¡¦ ones ¡V they trigger their production. Wounding, in effect, triggers a healing process.¡¨

In previous research, Yap discovered that mutant mice with a naturally defective tyk2 gene were immune to arthritis, a condition caused by inflammation. But these mutants were much more susceptible to opportunistic infections. Why? Without tyk2, Yap found, mice didn¡¦t make enough of the pro-inflammatory warriors that destroy harmful bugs and cause inflammation. This finding established the notion that tyk2 signaling controlled Interleukin 12, the furnace side of the system. But what controlled Interleukin 10, the air conditioner?

To find out, Yap and his team conducted a series of experiments in mutant mice infected with the parasite Toxoplasma gondii. They found that Interleukin 10 production by T helper 1 cells is triggered by Interferon-£^ƒnƒ{ƒnbut not directly. Another cell, an antigen presenting cell or APC, sends a stimulatory signal back to the T helper 1 cell, ordering it to make Interleukin 10.

¡§What we see is that the ¡¥hot¡¦ and ¡¥cool¡¦ arms of the immune system aren¡¦t independently regulated,¡¨ Yap said. ¡§They talk to each other and respond in a dynamic and coordinated fashion.¡¨

Yap said the findings should send a message to drug companies designing and testing tyk2-inhibiting medicines for arthritis and other autoimmune diseases. Block tyk2 function, Yap said, and patients will be more prone to infection ¡V and their arthritis may not be relieved. ¡§There could be a downside to these drugs,¡¨ he said.

Brown graduate student Michael Shaw and Brown Medical School student Mark Scott contributed to the research. Gordon Freeman of the Dana-Farber Cancer Institute, Barbara Fox and David Bzik of Dartmouth Medical School and Yasmine Belkaid of the National Institute of Allergy and Infectious Disease served as collaborators.

The National Institute of Allergy and Infectious Diseases funded the research.