Akt-dependent enhanced migratory capacity of Th17 cells from children with lupus nephritis

Sudhir Kshirsagar; Magdalena Riedl; Heiko Billing; Burkhard Tönshoff; Shanmugapriya Thangavadivel; Christian Steuber; Hagen Staude; Gottfried Wechselberger; Monika Edelbauer

doi:10.4049/jimmunol.1400044

Akt-dependent enhanced migratory capacity of Th17 cells from children with lupus nephritis

J Immunol. 2014 Nov 15;193(10):4895-903. doi: 10.4049/jimmunol.1400044. Epub 2014 Oct 22.

Authors

Sudhir Kshirsagar¹, Magdalena Riedl¹, Heiko Billing², Burkhard Tönshoff³, Shanmugapriya Thangavadivel⁴, Christian Steuber⁵, Hagen Staude⁶, Gottfried Wechselberger⁷, Monika Edelbauer⁸

Affiliations

¹ Department of Pediatrics I, Innsbruck Medical University, A-6020 Innsbruck, Austria;
² University Children's Hospital, Heidelberg, 69120 Heidelberg, Germany; University Children's Hospital, 72076 Tuebeingen, Germany;
³ University Children's Hospital, Heidelberg, 69120 Heidelberg, Germany;
⁴ Tyrolean Cancer Research Institute, Innsbruck Medical University, A-6020 Innsbruck, Austria;
⁵ Klinikum Links der Weser, 28277 Bremen, Germany;
⁶ Department of Pediatrics, University Children's Hospital, 18075 Rostock, Germany; and.
⁷ Department of Plastic, Aesthetic, and Reconstructive Surgery, Hospital of the Barmherzige Brüder Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria.
⁸ Department of Pediatrics I, Innsbruck Medical University, A-6020 Innsbruck, Austria; [email protected].

PMID: 25339666
DOI: 10.4049/jimmunol.1400044

Abstract

Th17 cells infiltrate the kidneys of patients with lupus nephritis (LN) and are critical for the pathogenesis of this disease. In this study, we show that enhanced activity of Stat3 in CD4(+)CD45RA(-)Foxp3(-) and Foxp3(low) effector T cells from children with LN correlates with increased frequencies of IL-17-producing cells within these T cell populations. The levels of retinoic acid-related orphan receptor c and IL-17 mRNA are significantly higher in PBMCs from children with LN than in those from controls. Mammalian target of rapamycin inhibition by rapamycin reduces both Stat3 activation in effector T cells and the frequency of IL-17-producing T cells in lupus patients. Complement factor C5a slightly increases the expression of IL-17 and induces activation of Akt in anti-CD3-activated lupus effector T cells. Th17 cells from children with LN exhibit high Akt activity and enhanced migratory capacity. Inhibition of the Akt signaling pathway significantly decreases Th17 cell migration. These findings indicate that the Akt signaling pathway plays a significant role in the migratory activity of Th17 cells from children with LN and suggest that therapeutic modulation of the Akt activity may inhibit Th17 cell trafficking to sites of inflammation and thus suppress chronic inflammatory processes in children with LN.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Cell Movement / drug effects
Child
Complement C5a / genetics
Complement C5a / immunology
Female
Forkhead Transcription Factors / deficiency
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / immunology
Gene Expression Regulation
Humans
Immunosuppressive Agents / pharmacology
Interleukin-17 / genetics
Interleukin-17 / immunology
Kidney / immunology
Kidney / pathology
Leukocyte Common Antigens / genetics
Leukocyte Common Antigens / immunology
Lupus Nephritis / genetics
Lupus Nephritis / immunology*
Lupus Nephritis / pathology
Male
Primary Cell Culture
Proto-Oncogene Proteins c-akt / genetics*
Proto-Oncogene Proteins c-akt / immunology
Receptors, Retinoic Acid / genetics
Receptors, Retinoic Acid / immunology
STAT3 Transcription Factor / genetics*
STAT3 Transcription Factor / immunology
Signal Transduction
Sirolimus / pharmacology
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / pathology
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / immunology
Th17 Cells / drug effects
Th17 Cells / immunology*
Th17 Cells / pathology

Substances

FOXP3 protein, human
Forkhead Transcription Factors
Immunosuppressive Agents
Interleukin-17
Receptors, Retinoic Acid
STAT3 Transcription Factor
STAT3 protein, human
Complement C5a
MTOR protein, human
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Leukocyte Common Antigens
Sirolimus