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A central paradigm in the field of lymphocyte biology asserts that replicatively senescent memory T cells express the carbohydrate epitope CD57. These cells nonetheless accumulate with age and expand numerically in response to persistent antigenic stimulation. Here, we use in vivo deuterium labeling and ex vivo analyses of telomere length, telomerase activity, and intracellular expression of the cell-cycle marker Ki67 to distinguish between two non-exclusive scenarios: (1) CD57 + memory T cells do not proliferate and instead arise via phenotypic transition from the CD57 - memory T cell pool; and/or (2) CD57 + memory T cells self-renew via intracompartmental proliferation. Our results provide compelling evidence in favor of the latter scenario and further suggest in conjunction with mathematical modeling that self-renewal is by far the most abundant source of newly generated CD57 + memory T cells. Immunological memory therefore appears to be intrinsically sustainable among highly differentiated subsets of T cells that express CD57., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)