Commensal bacteria drive B-cell lymphomagenesis in the setting of innate immunodeficiency.

Abstract

Myeloid cells are central players in innate immunity and inflammation. Their function is regulated by the adaptor protein TRAF3. We previously reported that aging myeloid cell-specific TRAF3-deficient (M-Traf3-/-) mice spontaneously develop chronic inflammation and B-cell lymphoma (BCL). Here we aimed to identify the internal trigger of this disease phenotype in these mice. We first detected gut microbiota dysbiosis and transmigration of commensal bacteria (CB) to the liver in aging M-Traf3-/- mice. Interestingly, depletion of CB using antibiotics effectively prevented BCL development in these mice. Systemic IgG responses against CB were induced and the IgH CDR3 sequences of malignant B-cell clones of M-Traf3 /- mice showed high homology to prevalent bacteria-reactive Ig clonotypes. Furthermore, M-Traf3-/- mice with BCL exhibited high serum titers of antibodies against CB. Together, our findings offer insights into the mechanisms underlying increased risks of B-cell lymphomagenesis observed in patients with compromised innate immunity.