Signaling molecule identified as essential for maintaining a balanced immune response

July 22, 2011

(MEMPHIS, Tenn. - July 22, 2011) St. Jude Children's Research Hospital investigators have identified a signaling molecule that functions like a factory supervisor to ensure that the right mix of specialized T cells is available to fight infections and guard against autoimmune disease.

The research also showed the molecule, phosphatase MKP-1, is an important regulator of immune balance. Working in laboratory cell lines and mice with specially engineered immune systems, scientists demonstrated that MKP-1 serves as a bridge between the innate immune response that is the body's first line of defense against infection and the more specialized adaptive immune response that follows. The results are published in the July 22 print edition of the scientific journal Immunity.

The results raise hopes that the MKP-1 pathway will lead to new tools for shaping the immune response, said Hongbo Chi, Ph.D., assistant member of the St. Jude Department of Immunology and the study's senior author. The co-first authors are Gonghua Huang, Ph.D., and Yanyan Wang, Ph.D., both postdoctoral fellows in Chi's laboratory.

The findings provide new details about how dendritic cells regulate the fate of naïve or undifferentiated T cells. Dendritic cells are the sentinels of the innate immune response, patrolling the body and ready to respond at the first sign of infection.

Investigators were surprised that a single molecule regulated production of three out of the four major subsets of T cells, which each play different roles. MKP-1 is a negative regulator of the enzyme p38, which is part of the MAP kinase family of enzymes that control pathways involved in cell proliferation, differentiation and death.

Chi and his colleagues demonstrated that MKP-1 works in dendritic cells by altering production of protein messengers known as cytokines. Those cytokines determine which subset of specialized T cells the undifferentiated T cells are fated to become. In this study, scientists showed that MKP1 controls production of the cytokines that yield T helper 1 (Th1), T helper 17 (Th17) and regulatory T (Treg) cells. Th1 cells combat intracellular bacterial and viral infections. Th17 cells fight extracellular bacterial infections and fungi. Treg cells help with immune suppression, protecting against autoimmune diseases.

The study showed that suppression of p38 by MKP-1 promotes production of interleukin 12 (IL-12), which leads to an increase in Th1 cells. Rising IL-12 coincides with a drop in interleukin 6 (IL-6) and a corresponding dip in production of Th17. MKP-1 also inhibited the generation of Treg cells by down-regulating production of a third cytokine, TGF-beta.

Knocking out MKP-1 in mice disrupted production of IL-12 and IL-6 in dendritic cells as well as the anti-bacterial and anti-fungal immune response, researchers reported. MKP-1 deficiency also promoted T-cell driven inflammation in a mouse model of colitis, an inflammatory disease.

"MKP-1 is the first signaling molecule found in dendritic cells to program differentiation of these diverse T- cell subsets," Chi said.

Previous work by other scientists focused on T cell differentiation in response to stimulation by cytokines. "This research fills a gap in our understanding of dendritic cell-mediated control of T-cell lineage choices," Chi said. "T cells do not recognize pathogens directly, but dendritic cells do. T cells need dendritic cells to tell them what to do. In this study, we show that MKP-1 signaling in dendritic cells bridges the innate and adaptive immune responses by regulating cytokine production."
-end-
Other authors are Lewis Shi and Thirumala-Devi Kanneganti, both of St. Jude.

The research was supported in part by the National Institutes of Health, the National Multiple Sclerosis Society, the Cancer Research Institute, The Hartwell Foundation and ALSAC.

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is internationally recognized for its pioneering research and treatment of children with cancer and other catastrophic diseases. Ranked one of the best pediatric cancer hospitals in the country, St. Jude is the first and only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. St. Jude has treated children from all 50 states and from around the world, serving as a trusted resource for physicians and researchers. St. Jude has developed research protocols that helped push overall survival rates for childhood cancer from less than 20 percent when the hospital opened to almost 80 percent today. St. Jude is the national coordinating center for the Pediatric Brain Tumor Consortium and the Childhood Cancer Survivor Study. In addition to pediatric cancer research, St. Jude is also a leader in sickle cell disease research and is a globally prominent research center for influenza.

Founded in 1962 by the late entertainer Danny Thomas, St. Jude freely shares its discoveries with scientific and medical communities around the world, publishing more research articles than any other pediatric cancer research center in the United States. St. Jude treats more than 5,700 patients each year and is the only pediatric cancer research center where families never pay for treatment not covered by insurance. St. Jude is financially supported by thousands of individual donors, organizations and corporations without which the hospital's work would not be possible. For more information, go to www.stjude.org.

St. Jude Children's Research Hospital

Related Immune Response Articles from Brightsurf:

Boosting chickens' own immune response could curb disease
Broiler chicken producers the world over are all too familiar with coccidiosis, a parasite-borne intestinal disease that stalls growth and winnows flocks.

Cells sacrifice themselves to boost immune response to viruses
Whether flu or coronavirus, it can take several days for the body to ramp up an effective response to a viral infection.

Children's immune response more effective against COVID-19
Children and adults exhibit distinct immune system responses to infection by the virus that causes COVID-19, a finding that helps explain why COVID-19 outcomes tend to be much worse in adults, researchers from Yale and Albert Einstein College of Medicine report Sept.

Which immune response could cause a vaccine against COVID-19?
Immune reactions caused by vaccination can help protect the organism, or sometimes may aggravate the condition.

Obesity may alter immune system response to COVID-19
Obesity may cause a hyperactive immune system response to COVID-19 infection that makes it difficult to fight off the virus, according to a new manuscript published in the Endocrine Society's journal, Endocrinology.

Immune response to Sars-Cov-2 following organ transplantation
Even patients with suppressed immune systems can achieve a strong immune response to Sars-Cov-2.

'Relaxed' T cells critical to immune response
Rice University researchers model the role of relaxation time as T cells bind to invaders or imposters, and how their ability to differentiate between the two triggers the body's immune system.

A novel mechanism that triggers a cellular immune response
Researchers at Baylor College of Medicine present comprehensive evidence that supports a novel trigger for a cell-mediated response and propose a mechanism for its action.

Platelets exacerbate immune response
Platelets not only play a key role in blood clotting, but can also significantly intensify inflammatory processes.

How to boost immune response to vaccines in older people
Identifying interventions that improve vaccine efficacy in older persons is vital to deliver healthy ageing for an ageing population.

Read More: Immune Response News and Immune Response Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.