Abstract
One of the hallmarks of the vertebrate adaptive immune system is the prolific expansion of individual cell clones that encounter their cognate antigen. More recently, however, there is growing evidence for the clonal expansion of innate lymphocytes, particularly in the context of pathogen challenge. Clonal expansion not only serves to amplify the number of specific lymphocytes to mount a robust protective response to the pathogen at hand but also results in selection and differentiation of the responding lymphocytes to generate a multitude of cell fates. Here, we summarize the evidence for clonal expansion in innate lymphocytes, which has primarily been observed in natural killer (NK) cells responding to cytomegalovirus infection, and consider the requirements for such a response in NK cells in light of those for T cells. Furthermore, we discuss multiple aspects of heterogeneity that both contribute to and result from the fundamental immunological process of clonal expansion, highlighting the parallels between innate and adaptive lymphocytes, with a particular focus on NK cells and CD8+ T cells.
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Acknowledgements
The authors apologize to those whose important contributions could not be discussed owing to space limitations. They thank K. Schober, V. Buchholz and L. Lanier for helpful discussions and reading of the manuscript. J.C.S. is supported by the Ludwig Center for Cancer Immunotherapy, the American Cancer Society, the Burroughs Wellcome Fund and the US National Institutes of Health (AI100874, AI130043 and P30CA008748).
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Glossary
- Clonal expansion
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The process by which individual antigen-specific innate and adaptive lymphocytes robustly proliferate following recognition of their cognate ligand, giving rise to a large pool of progeny that bear the same antigen specificity (clones). Clonal expansion coincides with selection and differentiation of the responding lymphocytes to generate a multitude of cell fates.
- Immunological memory
-
The ability of the immune system to quickly and specifically recognize an antigen that the body has previously encountered and initiate a more robust recall response. Although heightened responsiveness is a central feature of memory, true immunological memory is unique and requires that this results from antigen-specific clonal expansion and yields long-lived progeny. Although previously attributed solely to adaptive immune cells, we now appreciate that natural killer cells exhibit immunological memory, most clearly in the setting of cytomegalovirus infection.
- Epigenetic regulation
-
A combination of chromatin modifications (such as DNA methylation, histone post-translational modifications, chromatin accessibility and higher-order chromatin architecture) that regulate gene expression. The function of a given transcription factor depends not only on its expression but also on a favourable epigenetic state at regulatory elements that supports its binding and activity. Furthermore, transcription factors can reinforce their transcriptional programme by modifying the epigenetic landscape at their target genes.
- NK cell education
-
The process by which natural killer (NK) cells acquire functional competence. Education is contingent upon stochastically expressed inhibitory NK cell receptors engaging their ligand, self-MHC class I, thus ensuring that NK cells are sensitive to self-MHC class I. NK cell education is intricately linked to one prominent mechanism of NK cell-mediated cytotoxicity (that is, ‘missing self’ recognition), in which cells lacking self-MHC class I are susceptible to NK cell killing.
- Avidity
-
The overall binding to a specific target through multiple receptor–ligand interactions. This is in contrast to affinity, which describes the binding strength of a monomeric receptor–ligand interaction (as in a single T cell receptor–peptide–MHC). Increased avidity can be achieved through a higher density of cell surface receptors.
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Adams, N.M., Grassmann, S. & Sun, J.C. Clonal expansion of innate and adaptive lymphocytes. Nat Rev Immunol 20, 694–707 (2020). https://doi.org/10.1038/s41577-020-0307-4
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DOI: https://doi.org/10.1038/s41577-020-0307-4
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