All ETDs from UAB

Advisory Committee Chair

John D Mountz

Advisory Committee Members

Zdenek Hel

Peter D Burrows

Moon Nahm

Chander Raman

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


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.



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