Abatacept Limits Breach of Self-Tolerance in a Murine Model of Arthritis via Effects on the Generation of T Follicular Helper Cells

Abstract

Abatacept modulates CD28-mediated T cell costimulation and is efficacious in the treatment of rheumatoid arthritis (RA). Its mechanism of action has not been fully elucidated but will likely reveal critical pathologic pathways in RA. We show that abatacept substantially modulated Ag-specific T and B cell responses in vivo. Ag-specific T cell proliferation was reduced, and the acquisition of an activated phenotype, characterized by upregulation of CD69, OX40, ICOS, and programmed death-1 and downregulation of CD62L, was suppressed. Furthermore, abatacept suppressed the production of inflammatory cytokines, such as IFN-γ and IL-17. These effects were associated with a failure of Ag-specific T cells to acquire the CXCR5+ICOS+ T follicular helper cell phenotype. This, in turn, led to a failure of these cells to enter B cell follicles, resulting in reduced specific Ab responses, despite normal B cell clonal expansion. To test the pathologic significance of this, we used a novel model of RA associated with breach of self-tolerance to self-Ag and demonstrated that abatacept prevented the emergence of self-reactivity. Thus, CD28-dependent signaling is required for optimal T follicular helper cell maturation and expansion, and its inhibition prevents loss of self-tolerance in a model of articular pathology. Thus, we provide a novel mode of action for abatacept with profound implications for its potential usefulness in early inflammatory arthropathies associated with autoantibody expression.

Expansion of Tfh‐like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88‐deficient mice

“…Furthermore, dysregulation of Tfh cells or extrafollicular helper T cells has been linked with development of autoimmunity in several murine models of human lupus and rheumatoid arthritis [19,32,33]. In the present study, CD4 1 ICOS 1 PD-1 1 T cells expanded in RASV-administered MyD88 À/À mice were found to be a mixed population of both Tfh cells (CXCR5 1 ) and extrafollicular helper T cells (CXCR5 À ) (Fig.…”

“…Interestingly, a recent study showed that CTLA4-Ig, a promising treatment for rheumatoid arthritis, significantly reduced the upregulation of PD-1 and ICOS on Tfh cells in a murine model of arthritis [32,36], providing evidence for the relationship between abnormal Tfh cell activation and autoimmunity. Furthermore, CTLA4-Ig treatment reduced GC B-cell responses and prevented breach of Bcell tolerance [32], suggesting that CD28-dependent signaling is also required for optimal Tfh cell generation and that regulation of Tfh cell generation is important to prevent the onset of autoimmunity including autoantibody production.…”

“…Furthermore, CTLA4-Ig treatment reduced GC B-cell responses and prevented breach of Bcell tolerance [32], suggesting that CD28-dependent signaling is also required for optimal Tfh cell generation and that regulation of Tfh cell generation is important to prevent the onset of autoimmunity including autoantibody production.…”

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

“…To confirm the ability of abatacept to inhibit T cell priming (21,22), we investigated the activation status of T cells derived from the draining LNs of nonimmunized (naive), primed, primed and treated with abatacept or control IgG, and orally tolerized mice and analyzed the expression of CD44, CD62L, ICOS, and CD71 (Figure 1). Abatacept reduced the proportion of activated T cells (CD44 high CD62L-) and inhibited the up- Figure 1.…”

Angioimmunoblastic T-Cell Lymphoma with Polyarthritis Resembling Rheumatoid Arthritis

“…Novel therapies targeting Tfh cells currently undergoing pre-clinical evaluation and early phase clinical trials may potentially find a place in the treatment of Tfh lymphomas such as AITL. [14][15][16][17] …”