Defective germinal center B-cell response and reduced arthritic pathology in microRNA-29a-deficient mice

James Dooley, Josselyn E. Garcia-Perez, Jayasree Sreenivasan, Susan M. Schlenner, Roman Vangoitsenhoven, Aikaterini S. Papadopoulou, Lei Tian, Susann Schonefeldt, Lutgarde Serneels, Christophe Deroose, Kim A. Staats, Bart Van der Schueren, Bart De Strooper, Owen P. McGuinness, Chantal Mathieu and Adrian Liston

MicroRNA (miR) are short non-coding RNA sequences of 19-24 nucleotides that regulate gene expression by binding to mRNA target sequences. The miR-29 family of miR (miR-29a, b-1, b-2 and c) is a key player in T-cell differentiation and effector function, with deficiency causing thymic involution and a more inflammatory T-cell profile. However, the relative roles of different miR-29 family members in these processes have not been dissected. We studied the immunological role of the individual members of the miR-29 family using mice deficient for miR-29a/b-1 or miR-29b-2/c in homeostasis and during collagen-induced arthritis. We found a definitive hierarchy of immunological function, with the strong phenotype of miR-29a-deficiency in thymic involution and T-cell activation being reduced or absent in miR-29c-deficient mice. Strikingly, despite elevating the Th1 and Th17 responses, loss of miR-29a conferred near-complete protection from collagen-induced arthritis (CIA), with profound defects in B-cell proliferation and antibody production. Our results identify the hierarchical structure of the miR-29 family in T-cell biology, and identify miR-29a in B cells as a potential therapeutic target in arthritis.