The power and the promise of restimulation-induced cell death in human immune diseases.
Controlled expansion and contraction of lymphocytes both during and after an adaptive immune response are imperative to sustain a healthy immune system. Both extrinsic and intrinsic pathways of lymphocyte apoptosis are programmed to eliminate cells at the proper time to ensure immune homeostasis. Genetic disorders of apoptosis described in mice and humans have established Fas and Bim as critical pro-apoptotic molecules responsible for T-cell death in response to T-cell receptor restimulation and cytokine withdrawal, respectively. Emerging evidence prompts revision of this classic paradigm, especially for our understanding of restimulation-induced cell death (RICD) and its physiological purpose. Recent work indicates that RICD employs both Fas and Bim for T-cell deletion, dispelling the notion that these molecules are assigned to mutually exclusive apoptotic pathways. Furthermore, new mouse model data combined with our discovery of defective RICD in X-linked lymphoproliferative disease (XLP) patient T cells suggest that RICD is essential for precluding excess T-cell accumulation and associated immunopathology during the course of certain infections. Here, we review how these advances offer a refreshing new perspective on the phenomenon of T-cell apoptosis induced through antigen restimulation, including its relevance to immune homeostasis and potential for therapeutic interventions.
Snow
Andrew L
AL
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. snowa@niaid.nih.gov
Pandiyan
Pushpa
P
Zheng
Lixin
L
Krummey
Scott M
SM
Lenardo
Michael J
MJ
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D040181:Genetic Diseases, X-Linked; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000378:metabolism; D018448:Models, Immunological; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor