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Involvement of LEK1 in Dendritic Cell Regulation of T Cell Immunity against Chlamydia¹

Qing He^2,*,, Francis O. Eko^*, Deborah Lyn^*, Godwin A. Ananaba^*,, Claudiu Bandea, Joseph Martinez, Kahaliah Joseph, Kathy Kellar, Carolyn M. Black and Joseph U. Igietseme^*,

^* Morehouse School of Medicine, Atlanta, GA 30310; National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333; and Clark Atlanta University, Atlanta, GA 30314

We investigated the hypothesis that the enhanced Ag-presenting function of IL-10-deficient dendritic cells (DCs) is related to specific immunoregulatory cytoskeletal molecules expressed when exposed to Ags. We analyzed the role of a prominent cytoskeletal protein, LEK1, in the immunoregulation of DC functions; specifically cytokine secretion, costimulatory molecule expression, and T cell activation against Chlamydia. Targeted knockdown of LEK1 expression using specific antisense oligonucleotides resulted in the rapid maturation of Chlamydia-exposed DCs as measured by FACS analysis of key activation markers (i.e., CD14, CD40, CD54, CD80, CD86, CD197, CD205, and MHC class II). The secretion of mostly Th1 cytokines and chemokines (IL-1a, IL-9, IL-12, MIP-1a, and GM-CSF but not IL-4 and IL-10) was also enhanced by blocking of LEK1. The function of LEK1 in DC regulation involves cytoskeletal changes, since the dynamics of expression of vimentin and actin, key proteins of the cellular cytoskeleton, were altered after exposure of LEK1 knockdown DCs to Chlamydia. Furthermore, targeted inhibition of LEK1 expression resulted in the enhancement of the immunostimulatory capacity of DCs for T cell activation against Chlamydia. Thus, LEK1 knockdown DCs activated immune T cells at least 10-fold over untreated DCs. These results suggest that the effect of IL-10 deficiency is mediated through LEK1-related events that lead to rapid maturation of DCs and acquisition of the capacity to activate an elevated T cell response. Targeted modulation of LEK1 expression provides a novel strategy for augmenting the immunostimulatory function of DCs for inducing an effective immunity against pathogens.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Public Health Service grants (AI41231, GM 08248, and RR03034) from the National Institutes of Health and the Centers for Disease Control and Prevention.

² Address correspondence and reprint requests to Dr. Qing He, Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA 30310. E-mail address: qhe{at}msm.edu

³ Abbreviations used in this paper: DC, dendritic cell; WT, wild type; EB, elementary body; MoPN, mouse pneumonitis; 2-DE, two-dimensional gel electrophoresis; MHC II, MHC class II; MOI, multiplicity of infection.