The Protozoan Commensal Tritrichomonas Musculis is a Natural Adjuvant for Mucosal IgA

ABSTRACTImmunoglobulin(Ig) A antibodies are the most abundant antibodies supporting mucosal immune homeostasis and host-microbiota interactions. Driven by gut commensal microbes, IgA-secreting plasma cells (PC) differentiate through T cell-dependent (Td) or T cell independent (Ti) mechanisms. While commensal bacteria within the microbiota are known for their ability to promote IgA, the role of non-bacterial commensal microbes on the induction of IgA remains elusive. Here, we demonstrate that permanent colonization with the protozoan commensal Tritrichomonas musculis (T.mu) promotes T-cell dependent, IgA class-switch recombination and intestinal accumulation of IgA-secreting PC. T.mu colonization specifically drives the expansion of T follicular helper cells and a unique ICOS+ non-Tfh cell population, accompanied by an increase in germinal center B cells. Blockade of ICOS:ICOSL co-stimulation or MHCII-expression on B cells are central for the induction of IgA following colonization by T.mu, implicating a previously underappreciated mode of IgA induction following protozoan commensal colonization. Finally, the commensal T.mu further improves the induction of IgA-secreting plasma cells and their peripheral dissemination, even against non-protozoan, orally ingested antigens, identifying T.mu as natural adjuvant for IgA. Collectively, these findings propose a previously unknown, protozoa-driven mode of IgA induction that supports intestinal immune homeostasis even against non-microbial antigens.