The transcriptional repressor BLIMP1 curbs host defenses by suppressing expression of the chemokine CCL8.
The transcriptional repressor B lymphocyte-induced maturation protein 1 (BLIMP1) is a master regulator of B and T cell differentiation. To examine the role of BLIMP1 in innate immunity, we used a conditional knockout (CKO) of Blimp1 in myeloid cells and found that Blimp1 CKO mice were protected from lethal infection induced by Listeria monocytogenes. Transcriptome analysis of Blimp1 CKO macrophages identified the murine chemokine (C-C motif) ligand 8, CCL8, as a direct target of Blimp1-mediated transcriptional repression in these cells. BLIMP1-deficient macrophages expressed elevated levels of Ccl8, and consequently Blimp1 CKO mice had higher levels of circulating CCL8, resulting in increased neutrophils in the peripheral blood, promoting a more aggressive antibacterial response. Mice lacking the Ccl8 gene were more susceptible to L. monocytogenes infection than were wild-type mice. Although CCL8 failed to recruit neutrophils directly, it was chemotactic for γ/δ T cells, and CCL8-responsive γ/δ T cells were enriched for IL-17F. Finally, CCL8-mediated enhanced clearance of L. monocytogenes was dependent on γ/δ T cells. Collectively, these data reveal an important role for BLIMP1 in modulating host defenses by suppressing expression of the chemokine CCL8.
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605;
Martina
M
Severa
Sabina A
SA
Islam
Stephen N
SN
Waggoner
Zhaozhao
Z
Jiang
Nancy D
ND
Kim
Glennice
G
Ryan
Evelyn
E
Kurt-Jones
Israel
I
Charo
Daniel R
DR
Caffrey
Victor L
VL
Boyartchuk
Andrew D
AD
Luster
Katherine A
KA
Fitzgerald
D000818:Animals; D054412:Chemokine CCL8 / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology
C515454:Ccl8 protein, mouse; D054412:Chemokine CCL8; C513258:Prdm1 protein, mouse; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1