Date of Graduation

12-2014

Document Type

Dissertation (PhD)

Program Affiliation

Immunology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Dr. Chen Dong

Committee Member

Dr. Shao-Cong Sun

Committee Member

Dr. Stephanie S. Watowich

Committee Member

Dr. Stephen E. Ullrich

Committee Member

Dr. Gary E. Gallick

Abstract

THE ROLE OF DUAL SPECIFICITY PHOSPHATASE -11 IN INNATE AND ADAPTIVE IMMUNE RESPONSES

Kalyan Chakravarthy Nallaparaju, M.S.

Supervisory Professor: Chen Dong, Ph.D.

Dual-specificity phosphatases (DUSPs) constitute a subfamily of protein tyrosine phosphatases characterized by their ability to dephosphorylate both phosphotyrosine and phosphoserine/phosphothreonine residues within a substrate, typically among members of the MAP kinase family. DUSPs have been shown to play a critical role in the regulation of various cellular processes including signal transduction, cell cycle regulation and cellular proliferation via modulation of MAP kinase activities. Also, many members of this family have been demonstrated to be potent immune regulators. Deregulated expression patterns of DUSPs have been associated with pathogenesis in a wide range of diseases. DUSPs are broadly classified into six subgroups, of which the atypical subgroup of DUSPs is the least studied for their physiological functions.

DUSP11 is an atypical dual specificity phosphatase. Several recent in vitro studies highlighted the importance of this molecule in cell proliferation, cancer suppression and chronic inflammation. However, the physiological function of DUSP11 has not been studied via genetic approaches in vivo. Further, the role of DUSP11 in regulation of immune responses is not well understood. Our in vitro studies show that DUSP11 expression is induced after activation of innate and adaptive immune cells, suggesting that DUSP11 may play a role in the regulation of immune responses. To examine the function of DUSP11 in immune cells, we generated and analyzed Dusp11-/- mice. We hypothesized that DUSP11 is an essential regulator of innate and adaptive immune responses.

Interestingly, we found that Dusp11-/- mice were more susceptible to Listeria monocytogenes infection due to defective antigen-specific T cell responses when compared with wild-type mice. Further, Dusp11-/- mice were resistant to endotoxin-induced septic shock and Dusp11-/- dendritic cells had significantly decreased levels of pro-inflammatory cytokine production in response to TLR activation, associated with reduced NF-kB activation in vitro. Our mechanistic studies demonstrate that DUSP11 directly dephosphorylates the gamma binding domain (gbd) of IKK-b and thus positively regulates the activity of the IKK complex. Together, we demonstrate for the first time that DUSP11 is a critical regulator of immune responses and acts specifically by mediating IKK activation during innate immune responses. This phosphatase thus could serve as a novel target for therapeutic intervention for inflammatory and autoimmune diseases.

Keywords

DUSP, innate, adaptive, immune

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