The overall objective of this R21 application is to explore the role of ankyrin-repeat SOCS-box containing protein 2 (Asb2) in the regulation of CD4 helper T cell differentiation. Our previous studies have shown that the Asb2 gene is transcriptionally activated by Notch signaling and Asb2 mediates Notch-induced protein ubiquitination through bridging the formation of dimeric E3 ubiquitin ligase complexes. Asb2 promotes the degradation a large number of proteins including some related to T helper cell differentiation. Interestingly, genome-wide studies have revealed that Asb2 is highly expressed in Th2 cells and repressed in Treg cells. The interesting pattern of expression suggests a potential role for Asb2 in helper T cell differentiation. We hypothesize: (1) Asb2 is crucial for T2 differentiation and maintenance of Th2 lineage fate;(2) Asb2 favors T effector cell fates while suppressing Treg differentiation and destabilizing Treg identifies. We have already generated mouse models in which gain or loss of Asb2 function can be achieved via Cre- mediated recombination. These animal models will be used to test these hypotheses in two aims.
Aim1 will explore the role of Asb2 in Th2 differentiation and the stability of the Th2 fate. We will use Asb2 knockout mice to test if loss of Asb2 impairs Th2 differentiation in vitro or destabilizes the Th2 fate when switched to polarizing conditions for Th1, Th17 or Treg. We will then evaluate the role of Asb2 in Th2 responses in vivo by immunizing wild type and Asb2-/- mice with a parasite antigen, the soluble egg antigen (SEA) from Schistosoma mansoni or with OVA in alum. Th2 cytokine secretion and Th2-dependent Ig production in immunized mice will be measured.
Aim2 will explore the role of Asb2 in suppressing Treg differentiation. We will ectopically express Asb2 from the ROSA26 promoter in na?ve T cells and test if Asb2 can block iTreg differentiation in vitro or if Asb2 potentiates the conversion of Treg cells into Th1, Th2 and Th17 lineages. We will also examine Treg differentiation in vivo in Asb2-expressing mice and assess the ability of Asb2- expressing bone marrow to rescue the immune disorder caused by Foxp3-deficient scurfy bone marrow transplanted into RAG1 deficient hosts. Finding from these studies will provide an initial evaluation concerning the role of Asb2 in T helper cell differentiation and lay the ground work for a full-blown in-depth investigation. This line of investigation examines the regulation of T helper cell differentiation from a unique perspective, namely ubiquitin-mediated degradation of regulators of the differentiation. Fresh ideas will likely emerge from these studies that will be o therapeutic value in the contest of immunity and autoimmunity.

Public Health Relevance

The different types of T cells have to exist in harmony to ensure the body to mount proper defense against bacterial, viral and parasite infections. Dysregulation of the T cell reactions leads to asthma, inflammatory bowel diseases and multiple sclerosis. This study intends to examine a new mechanism that controls a fine balance of different T cell subsets.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Quill, Helen R
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Oklahoma Medical Research Foundation
Oklahoma City
United States
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