Abatacept Targets T Follicular Helper and Regulatory T Cells, Disrupting Molecular Pathways That Regulate Their Proliferation and Maintenance

Abstract

Abatacept is a CTLA-4-Ig fusion protein that binds to the costimulatory ligands CD80 and CD86 and blocks their interaction with the CD28 and CTLA-4 receptors expressed by T cells, therefore inhibiting T cell activation and function. Abatacept has shown clinical efficacy in treating some autoimmune diseases but has failed to show clinical benefit in other autoimmune conditions. The reasons for these disparate results are not clear and warrant further investigation of abatacept’s mode of action. Longitudinal specimens from the Immune Tolerance Network's A Cooperative Clinical Study of Abatacept in Multiple Sclerosis trial were used to examine the effects of abatacept treatment on the frequency and transcriptional profile of specific T cell populations in peripheral blood. We found that the relative abundance of CD4+ T follicular helper (Tfh) cells and regulatory T cells was selectively decreased in participants following abatacept treatment. Within both cell types, abatacept reduced the proportion of activated cells expressing CD38 and ICOS and was associated with decreased expression of genes that regulate cell-cycle and chromatin dynamics during cell proliferation, thereby linking changes in costimulatory signaling to impaired activation, proliferation, and decreased abundance. All cellular and molecular changes were reversed following termination of abatacept treatment. These data expand upon the mechanism of action of abatacept reported in other autoimmune diseases and identify new transcriptional targets of CD28-mediated costimulatory signaling in human regulatory T and Tfh cells, further informing on its potential use in diseases associated with dysregulated Tfh activity.

Failed, Interrupted, or Inconclusive Trials on Immunomodulatory Treatment Strategies in Multiple Sclerosis: Update 2015–2020

“…The observed effects could explain the poor efficacy in this cohort compared with reports on autoimmune conditions strongly associated with aberrant Tfh cell and plasmablast responses [49]. Further, a significant reduction in the relative frequency of CD45RO + memory Treg was detected [48]. These negative effects on Treg cells might impact the balance between effector and regulatory cell function and are detrimental to tolerance induction.…”

“…Interestingly, the cellular and molecular responses associated with abatacept therapy in both Treg and Tfh cells reversed upon discontinuation of treatment [48]. This reversal indicates that a co-stimulatory blockade does not lead to permanent reprogramming of these cells, providing a further explanation for why abatacept alone does not promote the development of sustained tolerance.…”

“…Despite its theoretical advantages and proven therapeutic efficacy in some immune-mediated diseases (e.g., RA), CTLA-4-Ig failed to show clinical benefits for other autoimmune conditions, including type 1 diabetes mellitus, lupus nephritis, and RRMS [46,48]. The ACCLAIM trial had shortcomings in study design.…”

“…Initially, a sample size of 123 patients had been defined to demonstrate a treatment effect of a 50% reduction in new GEL. Moreover, immunological changes in patients with RRMS participating in the ACCLAIM trial were subsequently analyzed to elucidate the cellular and molecular targets of a co-stimulatory blockade with CTLA-4-Ig [48]. Upon abatacept treatment, a transient decrease in circulating T follicular helper (Tfh) cells and plasmablasts was observed.…”

Transcriptomic profiling of human effector and regulatory T cell subsets identifies predictive population signatures

“…Because Treg cells are largely specific for either auto-antigens or for components of the microbiome present on barrier surfaces, they are subject to chronic stimulation and many of the genes previously associated with Treg cells are activation-induced genes that are not actually Treg cell specific (Pesenacker et al, 2016). Consistent with this, among genes more highly expressed in Treg cells, several were genes we previously found to be downregulated in subjects treated with the co-stimulation blocking drug abatacept (CTLA4-Ig) (Glatigny et al, 2019), including ARHGAP11A, CENPE, DUSP4, ERI1, GXYLT1, HELLS, NUSAP1, PMAIP1, SGMS1, and TOP2A ( Supplementary Table 1). To account for these and other activationinduced genes, Pesenacker et al compared the transcriptomes of resting and activated Th and Treg cells, and identified a 31-gene 'activation-independent' Treg cell signature (Pesenacker et al, 2016).…”