Evolution of Mucosal B Cell Immunity: Novel Roles of IgT+ B Cells in the Control of Host-pathogen Interactions

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

The mucosal surfaces of vertebrates such as the gut and mouth are inhabited by resident bacteria and also continuously exposed to invading microbes. Throughout evolution, specific types of antibodies have become specialized to protect such mucosal sites. In mammals and birds, immunoglobulin A (IgA) predominates at mucosal surfaces, whereas IgG and IgM provide systemic protection. While fish were thought to be devoid of antibodies dedicated to defend mucosal areas throughout the body, fish with true bones (teleost fish) have been recently found to contain an antibody molecule that is specialized to defend for the skin and gut areas. However, very little is still known about the function of this molecule and the cells producing it. This project proposes further studies on this area which will bring new insights into the evolution of mucosal immunity and its role in host-pathogen interactions in primitive vertebrates. Mucosal areas of fish, including the gut, skin and gills, represent the main areas through which pathogens infect these species. On a broader level beyond new basic scientific knowledge, these studies will benefit society by contributing to the aquaculture and fishing industries. By better understanding how fish defend these mucosal surfaces better tools to combat fish diseases can be developed. Until recently it was thought that mucosal immunoglobulins evolved from tetrapod species. Breaking this paradigm, trout IgT was shown to be an immunoglobulin specialized in gut mucosal immunity and concurrently, a new B cell subset was described uniquely expressing IgT. These findings have led to hypothesize a key role for IgT in mucosal immunity supported by the large numbers of IgT+ B cells that accumulate at sites of infection in both the gut and the skin that are pathogen-specific immunoglobulin (IgT) responses. Curiously, the IgT+ B cells express the highest levels of IL-10 of any other leukocyte. IL-10 is a key anti-inflammatory cytokine. Based on the unanticipated high IL-10 producing capacity of IgT+ B cells, it is now hypothesized that these cells play novel immunoregulatory functions in both mucosal and systemic organs upon pathogenic challenge. As these cells are crucial for producing pathogen-specific mucosal IgT responses, it is also hypothesized that IgT+ B cells play a pivotal role in the control and/or clearance of pathogens in mucosal surfaces. Utilizing a novel IgT+ B cell-depletion fish model, the project presents aims to assess the mechanistic basis of the inflammatory and regulatory responses in the depleted fish upon pathogenic challenge. The pathogens chosen for this purpose infect either skin only, gut only or produce systemic infections. Thus the investigators will be able to evaluate the IgT+ B cell contribution to pathogen control and clearance in animals infected with the pathogens and they will use illumina high throughput transcriptome sequencing analysis following infection. These combined approaches will illuminate the role of IgT positive B cells in teleost fish with differing pathogenic challenges.