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T-cell-targeted therapies in rheumatoid arthritis

Nature Clinical Practice Rheumatology volume 2, pages 201–210 (2006)Cite this article

Abstract

T cells regulate the disease process in rheumatoid arthritis (RA) on multiple levels and represent a logical choice for anti-inflammatory therapy. In the inflamed joint they promote neoangiogenesis and lymphoid organogenesis, and stimulate synoviocyte proliferation and development of bone-eroding osteoclasts. The design of T-cell-targeted therapies for RA needs to take into account the uniqueness of T-cell generation, turnover and differentiation in affected patients. Patients accumulate 'old' T cells that respond to alternate regulatory signals because of an accelerated immune aging process; any therapeutic interventions that increase the replicative stress of T cells should, therefore, be avoided. Instead, therapeutic approaches that raise the threshold for T-cell activation are more promising. As a rule, antigen-derived signals synergize with co-stimulatory signals to stimulate T cells; such co-stimulatory signals are now targeted in novel immunosuppressive therapies. An example is abatacept (soluble cytotoxic-T-lymphocyte-associated protein 4–immunoglobulin), which binds with high affinity to CD80/CD86 and effectively suppresses inflammatory activity in RA. The therapeutic benefits gained by disrupting T-cell co-stimulation indicate that the pathogenesis of RA is driven by a more generalized abnormality in T-cell activation thresholds rather than a highly selective action of arthritogenic antigens.

Key Points

  • T cells are key players in rheumatoid arthritis and, by virtue of their regulatory and effector functions, contribute to several disease pathways

  • T-cell activation requires integration of multiple signals, one of them deriving from antigen recognition and others from co-stimulatory receptors

  • Interfering with co-stimulatory signals can inhibit T-cell activation without the need to identify disease-relevant antigens

  • T-cell activation in rheumatoid arthritis occurs in the synovium as well as lymphoid organs, involving distinct co-stimulatory receptor–ligand pairs in each microenvironment

  • Patients with rheumatoid arthritis accumulate prematurely aged T cells that express novel regulatory receptors and respond to specific environmental cues

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Figure 1: T cells in rheumatoid arthritis.
Figure 2: Immunosuppressive mechanisms mediated by soluble cytotoxic T-lymphocyte-associated protein 4 immunoglobulin.
Figure 3: Central and peripheral T-cell co-stimulation.

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Acknowledgements

This work was funded in part by grants from the NIH. The authors thank Dr Sergey Pryshchep for preparing the figures and Tamela Yeargin for manuscript editing.

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  1. CM Weyand is the David Lowance Professor of Medicine and JJ Goronzy is the Mason Lowance Professor of Medicine. They co-direct the Kathleen B and Mason I Lowance Center for Human Immunology

Authors and Affiliations

  1. Department of Medicine, Emory School of Medicine, Atlanta, GA, USA

    Cornelia M Weyand & Jörg J Goronzy

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Correspondence to Cornelia M Weyand.

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Weyand, C., Goronzy, J. T-cell-targeted therapies in rheumatoid arthritis. Nat Rev Rheumatol 2, 201–210 (2006). https://doi.org/10.1038/ncprheum0142

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