'Hot' and 'Cold' Immune System Controlled by Same Agents

[Guest guest]

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

Brown University

PROVIDENCE, R.I. ¡X 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 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 Shaw and Brown Medical School student

Mark contributed to the research. Gordon Freeman of the Dana-

Farber Cancer Institute, Barbara Fox and 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.

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