Advisory Committee Chair
John D Mountz
Advisory Committee Members
Zdenek Hel
Peter D Burrows
Moon Nahm
Chander Raman
Document Type
Dissertation
Date of Award
2013
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Overreactivity of the germinal center (GC) is a central feature of autoantibody-mediated autoimmune diseases. Follicular T helper (Tfh) cells are the primary T helper subset that migrates to the incipient GC and forms close contacts with GC-B cells to promote GC formation and help GC-B cell differentiation, resulting in high-affinity antibody production. Increased levels of interleukin (IL)-21 and aberrant accumulation or function of Tfh cells have been associated with autoimmune disease severity in humans and lupus-prone mice. Follicular regulatory T (Tfr) cells are the regulatory T cell subset that also localizes in the GC and inhibits GC B cell differentiation. IL-21 plays a fundamental role for Tfh cell development but negatively regulates conventional regulatory T (Treg) cells. In addition, the pro-inflammatory cytokine IL-17 also has been shown to promote GC development and autoantibody production. In the current study, we demonstrated increased levels of serum IL-21 and accumulation of Tfh cells in autoimmune BXD2 mice, which have a high level of IL-17 in sera and spontaneously develop GC containing autoantibody-producing cells. Deficiency of IL-21 or IL-17 resulted in impaired GC formation in BXD2 mice. Tfh cells in BXD2 mice consisted of distinct IL-21- and IL-17-producing subpopulations. IL-21 primarily promoted Tfh cell development but inhibited Tfr cell commitment, thereby leading to an imbalance of Tfr/Tfh in BXD2 mice. IL-21 also converted Tfr cells into non-Tfr cells and counteracted Tfr-mediated inhibition on Tfh cells and B cells. Therefore, Tfr cells in BXD2 mice were defective in frequency and suppressive function that may regulate GC formation in the mice. In addition, IL-21 promoted IL-17 production and IL-17R expression by Tfh cells, which prepared Tfh cells for the IL-17 regulation. IL-17 then sequentially up-regulated regulator of G-protein signaling (RGS)-16 and co-stimulatory molecules to exert a unique function by stabilizing Tfh cells in GC light zone (LZ) to form close contact with GC B cells. The study suggests a novel two-checkpoint model for regulating Tfh cells in murine autoimmunity, namely the number of differentiated Tfh cells and their physical stabilization in GC LZ. IL-21 and IL-17 acted at each checkpoint to enable pathogenic GC development in BXD2 mice.
Recommended Citation
Ding, Yanna, "The Role Of Il-21 And Il-17 In Regulating Follicular T Helper Cells In Germinal Center Response Of Autoimmunity" (2013). All ETDs from UAB. 1526.
https://digitalcommons.library.uab.edu/etd-collection/1526