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Ex Vivo Homeostatic Proliferation of CD4⁺ T Cells in Rheumatoid Arthritis Is Dysregulated and Driven by Membrane-Anchored TNF¹

Department of Medicine IV, University of Leipzig, Leipzig, Germany

The systemic CD4⁺ T cell compartment in patients with rheumatoid arthritis (RA) is characterized by TCR repertoire contraction, shortened telomere lengths, and decreased numbers of recent thymic emigrants, suggesting a disturbed CD4⁺ T cell homeostasis. In mice, homeostatic proliferation of peripheral CD4⁺ T cells is regulated by TCR interaction with self peptide-MHC complexes (pMHC) and can be reproduced in vitro. We have established an ex vivo model of homeostatic proliferation, in which self-replication of human CD4⁺ T cells is induced by cell-cell contact with autologous monocytes. In healthy individuals, blockade of TCR-pMHC class II contact resulted in decreased CD4⁺ T cell division. In contrast, homeostatic proliferation in RA patients was not inhibited by pMHC blockade, but increased during the initial culture period. The anti-TNF- Ab cA2 inhibited homeostasis-driven ex vivo proliferation in healthy controls and in RA patients. In addition, treatment of RA patients with infliximab decreased the ex vivo rate of homeostatic proliferation of CD4⁺ T cells. Our results suggest a disturbed regulation of CD4⁺ T cell homeostasis leading to the repertoire aberrations reported in RA. Membrane-anchored TNF- appears to be a cell-cell contact-dependent stimulus of homeostatic proliferation of CD4⁺ T cells, possibly favoring self-replication of autoreactive CD4⁺ T cells in patients with RA.

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