Helper T-cell migration and infiltration in central nervous system are critical events in multiple sclerosis (MS) and its animal model of experimental autoimmune encephalomyelitis (EAE). Our preliminary results show that mice deficient in transcription factor Bcl11b in mature T cells showed reduced EAE severity with delayed onset, caused by diminished helper T-cell infiltration in the CNS. Instead helper T cells accumulated in the gut, however without causing overt inflammatory bowel disease. We propose studies to decipher the molecular mechanisms underlying the diversion of the Bcl11b-deficient CD4+ T cells from the draining lymph nodes and central nervous system, whichwill open new avenues for multiple sclerosis therapies, and other autoimmune disorders. Additionally, these studies are of major importance because they will further our understanding of the network of transcription factors that control effector CD4+ T cell differentiation and functional plasticity. Specifically, our studies will reveal the relationship between the transcription factors Bcl11b, Rorgt and Gata3 in Th17 lineage differentiation, Bcl11b, Gata3 and Rorgt in Th2 lineage differentiation, and how these two alternate lineages influence each other to maintain the balance between specialization and plasticity.

Public Health Relevance

An optimal helper T cell immune response requires two critical events: (1) efficient production of the appropriate cytokines, necessary to contain an offending organism by regulating other immune cells;(2) efficient migration of effector CD4+ T cells to the specific site of inflammation, and not to other sites. Deciphering the molecular mechanisms underlying these two processes is essential for the development of therapies able to elicit protective immune responses, while blocking those detrimental to the host, such as those in multiple sclerosis and other autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067846-08
Application #
8602791
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Quill, Helen R
Project Start
2005-12-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Albany Medical College
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12208
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