Peroxisome proliferator-activated receptor alpha deficiency impairs regulatory T cell functions: Possible application in the inhibition of melanoma tumor growth in mice.
Regulatory T (Treg) cells are important to induce and maintain immunological self-tolerance. Although the progress accomplished in understanding the functional mechanism of Treg cells, intracellular molecules that control the mechanisms of their suppressive capacity are still on investigation. The present study showed that peroxisome proliferator-activated receptor-alpha deficiency impaired the suppressive activity of Treg cells on CD4+CD25-and CD8+T cell proliferation. In Treg cells, PPARα gene deletion also induced a decrease of migratory abilities, and downregulated the expression of chemokine receptors (CCR-4, CCR-8 and CXCR-4) and p27KIP1mRNA. Treg cells from PPARα-/-mice also lost their anergic property. Since low Treg activity, as observed in PPARα-/-mice, is known to be associated with the inhibition of tumor growth, we inoculated these mice with B16 melanoma cells and assessed tumor proliferation. In PPARα-/-mice, cancer growth was significantly curtailed, and it was correlated with high expression of granzyme B and perforin mRNA in tumor bed. Degranulation of cytolytic molecules by CD8+T cells, assessed by a perforin-release marker CD107a expression, was higher in PPARα-/-mice than that in wild-type mice. Tumor-infiltrating lymphocytes (TIL) in melanoma tumors in PPARα-/-mice exhibited high pro-inflammatory Th1 phenotype. Consistently, adoptive transfer into lymphopenic RAG2-/-mice of total PPARα-/-splenic T cells inhibited more the growth rate of B16 tumor than the wild type splenic T cells. Our findings suggest that PPARα deficiency, by diminishing Treg cell functions and upregulating pro-inflammatory T cell phenotype, exerts an in vivo anti-cancer properties.
University of Burgundy, INSERM U866, Faculty of Life Sciences, Dijon, France. Electronic address: aziz.hichami@u-bourgogne.fr.
Aziz
A
Hichami
University of Abomey-Calavi, Laboratory of Cell Biology and Physiology, Institute of Applied Biomedical Sciences (ISBA), Faculty of Sciences and Techniques, Cotonou, Benin. Electronic address: yeskad2001@yahoo.fr.
Akadiri
A
Yessoufou
University of Burgundy, INSERM U866, Faculty of Life Sciences, Dijon, France. Electronic address: fghiringhelli@cgfl.fr.
François
F
Ghiringhelli
University of Burgundy, INSERM U866, Faculty of Life Sciences, Dijon, France. Electronic address: francoise.salvadori@u-bourgogne.fr.
Françoise
F
Salvadori
University of Abomey-Calavi, Laboratory of Cell Biology and Physiology, Institute of Applied Biomedical Sciences (ISBA), Faculty of Sciences and Techniques, Cotonou, Benin. Electronic address: kamoutairo@yahoo.fr.
Kabirou
K
Moutairou
University of Burgundy, INSERM U866, Faculty of Life Sciences, Dijon, France. Electronic address: narcisse.zwetyenga@chu-dijon.fr.
Narcisse
N
Zwetyenga
University of Burgundy, INSERM U866, Faculty of Life Sciences, Dijon, France. Electronic address: Naim.Khan@u-bourgogne.fr.
Naim Akhtar
NA
Khan
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016219:Immunotherapy, Adoptive / Q000379:methods; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics*; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D047368:Tumor Burden / Q000235:genetics*
D004268:DNA-Binding Proteins; D047493:PPAR alpha; C499308:Rag2 protein, mouse; D019707:Receptors, Chemokine
B16 melanoma tumor; CD4(+)CD25(+) regulatory T cells; PPARα; Perforin