The Role of the Akt2 Isoform in Th17 Differentiation in Vitro and Peripheral Cd4 T Cell Immune Responses in Vivo

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Doctor of Philosophy (PhD)
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Cell & Molecular Biology
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Akt
CD4 T cells
experimental autoimmune enchephalomyelitis
Th17 cells
Allergy and Immunology
Immunology and Infectious Disease
Medical Immunology
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2015-11-16T00:00:00-08:00
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Abstract

Akt1 and Akt2, isoforms of the serine threonine kinase Akt, are essential for T cell development. However, their role in peripheral T cell differentiation remains undefined. Using germline deletions of either Akt1 or Akt2 in mice, we found that while both are important for Th17 differentiation, the impact of Akt2 loss was greater. Mechanistically, while Akt2-/- Th17 cells were predicted by microarray analysis to have suppressed cholesterol biosynthetic and Il-6 signaling pathways, neither pathway emerged as the primary mechanism through which Akt2 contributes to Th17 differentiation. We also interrogated the role of the well-known Akt target, mTORC1, and found that Akt2-/- Th17 cells were equally sensitive to inhibition of the mTORC1-S6K axis as their WT counterparts. However, Akt2 deficiency was associated with elevated Gfi1 mRNA, which encodes for a known inhibitor of Th17 differentiation, and decreased mir155, which encodes for a miRNA that promotes Th17 differentiation. Furthermore, Akt2 loss has significant in vivo consequences and results in a dampened peripheral T cell response to myelin oligodendrocyte glycoprotein (MOG) immunization. This dampened response was associated with altered Th cell differentiation including a pronounced diminution of inflammatory cytokine production and preferential expansion of regulatory T cells compared to non-T regulatory cells. Using mice with Akt2 loss only in the T cell compartment, Akt2 cKO, we demonstrate that Akt2 promotes Th17 differentiation in both a T cell-intrinsic and T cell-extrinsic manner; Akt2 cKO CD4 T cells had defective IL-17A production in vitro although this defect was milder than that observed in Akt2-/- cells. In vivo, Akt2 cKO splenocytes trended towards decreased cytokine production compared to their WT counterparts after immunization with MOG peptide, suggesting a significant role for Akt2 in non-T cells in shaping the peripheral CD4 T cell response in this model system. Taken together, we identify Akt2 as an important signaling molecule in regulating peripheral CD4 T cell responses. Future studies interrogating the in vivo impact of Akt2 loss in other experimental systems that rely on CD4 T helper cell mediated immunity would provide insight into the contributions of Akt2 to CD4 Th cell differentiation.

Advisor
Gary A. Koretzky
Martha S. Jordan
Date of degree
2014-01-01
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