Loss of T cell microRNA provides systemic protection against autoimmune pathology in mice.
With an increasing number of studies demonstrating alterations in T cell microRNA expression during autoimmune disease, modulation of the T cell microRNA network is considered a potential therapeutic strategy. Due to the complex and often opposing interactions of individual microRNA, prioritization of therapeutic targets first requires dissecting the dominant effects of the T cell microRNA network. Initial results utilizing a unidirectional screen suggested that the tolerogenic functions were dominant, with spontaneous colitis resulting from T cell-specific excision of Dicer. Here we performed a bidirectional screen for microRNA function by removing Dicer from the T cells of both wildtype mice and Transforming Growth Factor β (TGFβ) receptor-deficient mice. This allowed the impact of microRNA loss on T cell activation, effector T cell differentiation and autoimmune pathology to be systematically assessed. This bidirectional screen revealed a dominant immunogenic function for T cell microRNA, with potent suppression of T cell activation, IFNγ production and autoimmune pathology in all targeted organs except the colon, where Dicer-dependent microRNA demonstrated a dominant tolerogenic function. These results reverse the original conclusions of microRNA function in T cells by revealing a systemic pro-autoimmune function.
Autoimmune Genetics Laboratory, VIB and University of Leuven, Leuven, Belgium. lei.tian@student.kuleuven.be
Lei
L
Tian
Gert
G
De Hertogh
Maya
M
Fedeli
Kim A
KA
Staats
Susann
S
Schonefeldt
Stephanie
S
Humblet-Baron
Ludo
L
Van Den Bosch
Paolo
P
Dellabona
James
J
Dooley
Adrian
A
Liston
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D053263:Gene Regulatory Networks; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000172:deficiency / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism
D016207:Cytokines; D035683:MicroRNAs; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases