The Role of Follicular Helper T Cell Molecules and Environmental Influences in Autoantibody Production and Progression to Inflammatory Arthritis in Mice

Abstract

Objective Antibody‐mediated autoimmunity involves cognate interactions between self‐reactive T cells and B cells during germinal center (GC) reactions. The aim of this study was to determine the role of essential follicular helper T (Tfh) cell molecules (CXCR5, signaling lymphocytic activation molecule–associated protein) on autoreactive CD4+ cells and the role of certain environmental influences that may determine GC‐driven autoantibody production and arthritis development. Methods We transferred self‐reactive CD4+ cells from KRN‐Tg mice into recipient mice, which induced autoantibodies and autoinflammatory arthritis. This model allowed manipulation of environmental effects, such as inflammation, and use of transferred cells that were genetically deficient in important Tfh cell–associated molecules. Results A deficiency of signaling lymphocytic activation molecule–associated protein (SAP) in CD4+ cells from KRN‐Tg mice completely protected against arthritis, indicating that stable T cell–B cell interactions are required for GC formation, autoantibody production, and arthritis induction. In contrast, a CXCR5 deficiency in CD4+ cells from KRN‐Tg mice still induced disease when these cells were transferred into wild‐type mice, suggesting that T cell help for B cells could rely on other migration mechanisms. However, various manipulations influenced this system, including elimination of bystander effects through use of CD28−/− recipient mice (reduced disease) or use of inflammation‐inducing Freund's complete adjuvant (progression to arthritis). We also examined the capacity of preexisting GCs with a nonautoimmune specificity to co‐opt autoimmune T cells and observed no evidence for any influence. Conclusion In addition to the quality and quantity of cognate CD4+ cell help, external factors such as inflammation and noncognate CD4+ cell bystander activation trigger autoimmunity by shaping events within autoimmune GC responses. SAP is an essential molecule for autoimmune antibody production, whereas the importance of CXCR5 varies depending on the circumstances.

Adenosine 2a Receptor Signal Blockade of Murine Autoimmune Arthritis via Inhibition of Pathogenic Germinal Center–Follicular Helper T Cells

“…Preclinical studies using a mouse model of autoimmune arthritis have indicated that Tfh and GC‐Tfh cells contribute to the formation of GCs, production of high‐affinity autoantibodies, and clinical manifestations of arthritis . Consistent with this, T cell–specific deficiencies in Tfh molecules, such as CXCR5, signaling lymphocytic activation molecule–associated protein, and interleukin‐21 (IL‐21), can protect against the development of severe arthritis in mice .…”

T Cell/B Cell Collaboration and Autoimmunity: An Intimate Relationship

“…In a separate mouse model, microarray analysis of T cells responding to pancreatic antigen revealed a striking signature for Tfh differentiation, and cells with a Tfh phenotype showed an enhanced capacity to induce diabetes upon adoptive transfer (72). SAP dependent T cell/B cell interactions have been shown to be essential in the K/BxN model of arthritis (73), where a role for gut microbiota in promoting disease via Tfh induction has been identified (74). A separate study revealed that collagen-induced arthritis could be ameliorated by T cell specific CXCR5 deficiency consistent with the potential involvement of Tfh (75).…”

Potential involvement of OX40 in the regulation of autoantibody sialylation in arthritis

“…In a patient with RA, an increased frequency of circulating Tfh cells in the peripheral blood that correlate with serum ACPA levels and disease severity was reported 16. In RA mouse models, there are several reports that show the increase of Tfh cells in secondary lymphoid organs 17 18. From these reports, Tfh cells could have an essential role in RA pathogenesis; however, it is not completely elucidated.…”