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J Immunol. 2019 Mar 1;202(5):1373-1382. doi: 10.4049/jimmunol.1801425. Epub 2019 Jan 25.

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

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Immunology Program, Benaroya Research Institute, Seattle, WA 98101.
Department of Immunology, University of Washington, Seattle, WA 98109.
Immune Tolerance Network, University of California San Francisco, San Francisco, CA 94107.
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Abu Haidar Neuroscience Institute, American University of Beirut, Beirut 1107 2020, Lebanon.
National Institute of Allergy and Infectious Diseases, Division of Allergy, Immunology, and Transplantation, Rockville, MD 20852.
Immune Tolerance Network, Bethesda, MD 20814; and.
Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA 02129.
Immunology Program, Benaroya Research Institute, Seattle, WA 98101;


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.


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