Molecular Drivers of Lymphocyte Organization in Vertebrate Mucosal Surfaces: Revisiting the TNF Superfamily Hypothesis

Abstract

The adaptive immune system of all jawed vertebrates relies on the presence of B and T cell lymphocytes that aggregate in specific body sites to form primary and secondary lymphoid structures. Secondary lymphoid organs include organized MALT (O-MALT) such as the tonsils and Peyer patches. O-MALT became progressively organized during vertebrate evolution, and the TNF superfamily of genes has been identified as essential for the formation and maintenance of O-MALT and other secondary and tertiary lymphoid structures in mammals. Yet, the molecular drivers of O-MALT structures found in ectotherms and birds remain essentially unknown. In this study, we provide evidence that TNFSFs, such as lymphotoxins, are likely not a universal mechanism to maintain O-MALT structures in adulthood of teleost fish, sarcopterygian fish, or birds. Although a role for TNFSF2 (TNF-a) cannot be ruled out, transcriptomics suggest that maintenance of O-MALT in nonmammalian vertebrates relies on expression of diverse genes with shared biological functions in neuronal signaling. Importantly, we identify that expression of many genes with olfactory function is a unique feature of mammalian Peyer patches but not the O-MALT of birds or ectotherms. These results provide a new view of O-MALT evolution in vertebrates and indicate that different genes with shared biological functions may have driven the formation of these lymphoid structures by a process of convergent evolution.

High-Resolution, 3D Imaging of the Zebrafish Gill-Associated Lymphoid Tissue (GIALT) Reveals a Novel Lymphoid Structure, the Amphibranchial Lymphoid Tissue

“…The organization of the mucosal immune system in mammals is thought to support efficient antigen trapping and rapid activation of the adaptive immune response ( 82 ). Organized-MALT (O-MALT) in mammals include Peyer’s patches in the gut and tonsils in the naso-pharyngeal cavity.…”

Identification of a pharyngeal mucosal lymphoid organ in zebrafish and other teleosts: Tonsils in fish?

“…Recent studies have also reported the existence of a MALT associated with the mouth and the pharynx ( 32 , 33 ). In mammals, the organization of MALTs is well defined into regions where disorganized immune cells are scattered, hence forming a diffuse mucosal immune system, and into organized lymphoid aggregates such as Peyer’s patches in the gut and Waldeyer’s ring of tonsils in the nasopharyngeal area ( 34 ). In contrast, the fish mucosal immune system has long been perceived as a set of scattered immune cells spread along mucosal territories ( 19 , 27 ).…”