Immune System – First Response – Foxp1

Faster, Higher, Stronger: The Protein that Enables Powerful Initial Immune Response

http://www.wistar.org

Wistar Findings Suggest Means of Boosting Initial Immune Response 

 Your first response to an infectious agent or antigen ordinarily takes about a week, and is relatively weak. However, if your immune system encounters that antigen a second time, the so-called memory response is rapid, powerful, and very effective.

Now, a team of researchers at The Wistar Institute offers evidence that a protein, called Foxp1, is a key component of these antibody responses. Manipulating this protein’s activity, they say, could provide a useful pathway to boosting antibody responses to treat infectious diseases, for example, or suppressing them to treat autoimmune disorders. Their findings appear online in the journal Nature Immunology.

“Foxp1 has an important role in our antibody immune responses, and if we could find a way to regulate Foxp1 activity in a subset of T cells, the CD4+ T cells, it could have some profound impact on the antibody responses,” said Hui Hu, Ph.D., senior author of the study and associate professor at Wistar’s National Cancer Institute-designated Cancer Center.

“Repressing Foxp1 activity, for example, we may be able to make antibody responses faster-acting and more effective, which could be crucial in, say, a pandemic when time is a critical factor,” Hu said. “Alternatively, if we could enhance the effectiveness of this protein, we may be able to significantly dampen the antibody responses that are unwanted in some cases of autoimmune diseases such as lupus.”

Previously, the Hu laboratory determined that Foxp1 was responsible for keeping T cells—the white blood cells that mediate our immune system—on “active stand-by mode,” a process called quiescence. In the present study, Hu teamed with the laboratories of Louise C. Showe, Ph.D., professor in the Wistar Cancer Center’s Molecular and Cellular Oncogenesis program, which provided crucial genomics expertise, and Jan Erickson, Ph.D., professor in the Tumor Microenvironment and Metastasis program, which offered expertise in the study of autoimmunity and the activation of B cells, the cells that generate antibodies.

According to their Nature Immunology report, variants (or isoforms) of Foxp1 (called Foxp1A and Foxp1D) are critical regulators for the formation of a type of T cells, called T Follicular Helper (TFH) cells. These TFH cells then go on to enable B cells in creating long-lived, highly reactive antibodies.  The proteins are transcription factors, meaning they work by binding to DNA to control which genes in these T cells are “read” or translated into protein.

In the initial days of an immune response, the Foxp1 proteins determine how TFH cells arise from activated T cells. “The two isoforms act as regulators of TFH differentiation in the early moments of the immune response, where they effectively act as gatekeepers to slow TFH development, ” Hu said. “They constitute a ‘double-check’ system that prevents the humoral branch of the immune system from acting too hastily.”

Funding for this study was provided by the National Institutes of Health (including the following grants: AI095439, AI103162, CA132098, 1S10RR024693, CA31534, AI083022, 5DP5OD012146, AI063107), Alliance for Cancer Gene Therapy (ACGT) Foundation, WAWA, Martha W. Rogers Trust, and the Wistar Cancer Center (P30 CA10815).

Wistar collaborators also include, Haikun Wang, Ph.D., Jianlin Geng Ph.D., Xiaomin Wen, Ph.D., Enguang Bi, Ph.D., Andrew V. Kossenkov, Ph.D., Amaya I. Wolf, Ph.D., Hiroshi Takata, Ph.D., Timothy J. Day, Li-Yuan Chang, Ph.D., Stephanie L. Sprout, Emily K. Becker, Jessica Willen, Lifeng Tian, Ph.D., Xinxin Wang, and Ping Jiang, Ph.D. Co-authors also include Gabriel D. Victora, Ph.D., and Jeroen Tas, from the Whitehead Institute for Biomedical Research; Shane Crotty, Ph.D. and Youn Soo Choi, Ph.D., from the La Jolla Institute for Allergy & Immunology; Changchun Xiao, Ph.D., from The Scripps Research Institute; and Haley O. Tucker, Ph.D. from the University of Texas at Austin.

The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. The Wistar Institute: Today’s Discoveries – Tomorrow’s Cures. On the Web at www.wistar.org.

————————-

Further Readings of Interest

https://asdresearchinitiative.wordpress.com/?s=fox

The DISC1 promoter: characterization and regulation by FOXP2.

http://www.ncbi.nlm.nih.gov/pubmed/22434823

Medical Genetics Section, Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.

Abstract

Disrupted in schizophrenia 1 (DISC1) is a leading candidate susceptibility gene for schizophrenia, bipolar disorder and recurrent major depression, which has been implicated in other psychiatric illnesses of neurodevelopmental origin, including autism.

DISC1 was initially identified at the breakpoint of a balanced chromosomal translocation, t(1;11) (q42.1;14.3), in a family with a high incidence of psychiatric illness. Carriers of the translocation show a 50% reduction in DISC1 protein levels, suggesting altered DISC1 expression as a pathogenic mechanism in psychiatric illness. Altered DISC1 expression in the post-mortem brains of individuals with psychiatric illness and the frequent implication of non-coding regions of the gene by association analysis further support this assertion.

Here, we provide the first characterization of the DISC1 promoter region. Using dual luciferase assays, we demonstrate that a region -300 to -177 bp relative to the transcription start site (TSS) contributes positively to DISC1 promoter activity, while a region -982 to -301 bp relative to the TSS confers a repressive effect.

We further demonstrate inhibition of DISC1 promoter activity and protein expression by forkhead-box P2 (FOXP2), a transcription factor implicated in speech and language function.

This inhibition is diminished by two distinct FOXP2 point mutations, R553H and R328X, which were previously found in families affected by developmental verbal dyspraxia.

Our work identifies an intriguing mechanistic link between neurodevelopmental disorders that have traditionally been viewed as diagnostically distinct but which do share varying degrees of phenotypic overlap.

 

Advertisements
This entry was posted in Autism, co-morbid, Environment, Immune System, Inflammation, Neurology, Physiology, Schizophrenia, Treatment. Bookmark the permalink.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s