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Regulation of activated T cell survival in rheumatic autoimmune diseases

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From Nature Reviews Rheumatology

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Abstract

Adaptive immune responses rely on the proliferation of T lymphocytes able to recognize and eliminate pathogens. The magnitude and duration of the expansion of activated T cell clones are finely regulated to minimize immunopathology and avoid autoimmunity. In patients with rheumatic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, activated lymphocytes survive and exert effector functions for prolonged periods, defying the mechanisms that normally curb their capacities during acute and chronic infections. Here, we review the molecular mechanisms that limit the duration of immune responses in health and discuss the factors that alter such regulation in the setting of systemic lupus erythematosus and rheumatoid arthritis. We highlight defects that could contribute to the development and progression of autoimmune disease and describe how chronic inflammation can alter the regulation of activated lymphocyte survival, promoting its perpetuation. These concepts might contribute to the understanding of the mechanisms that underlie the chronicity of inflammation in the context of autoimmunity.

Key points

  • Chronic target-organ inflammation directly affects disease expression.

  • The quantity and temporality of antigen modulates the ensuing immune response.

  • The balance between stemness and exhaustion might underlie the chronicity of self-directed immune responses.

  • Resistance to apoptosis and/or exhaustion might enable self-reactive T cells to persist in target organs and perpetuate local disease.

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Fig. 1: Proliferation and apoptosis determine the magnitude and length of immune responses.
Fig. 2: Cytokines and other environmental stimuli regulate activated T cell survival.
Fig. 3: Antigen abundance and persistence induce exhaustion and limit pro-inflammatory functions in T cells.
Fig. 4: Proposed mechanisms that promote T cell survival in the setting of autoimmune disease and possible therapeutic targets.
Fig. 5: Persistently expressed antigens induce T cell inactivation through different mechanisms.

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Acknowledgements

Work performed in the authors’ laboratories was funded by the Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico, grants FORDECYT 303046 (JCC), FORDECYT 303067 (FR), and Ciencia de Frontera 2019-1564468 (IKMS).

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  1. Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

    Florencia Rosetti, Iris K. Madera-Salcedo & José C. Crispín

  2. Medical Research Council, Laboratory of Molecular Biology, Cambridge, UK

    Noé Rodríguez-Rodríguez

  3. Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico

    José C. Crispín

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Rosetti, F., Madera-Salcedo, I.K., Rodríguez-Rodríguez, N. et al. Regulation of activated T cell survival in rheumatic autoimmune diseases. Nat Rev Rheumatol 18, 232–244 (2022). https://doi.org/10.1038/s41584-021-00741-9

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