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The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells Wilfred Ndifon and Jonathan Dushoff This information is current as J Immunol published online 13 May 2016 of September 27, 2021. http://www.jimmunol.org/content/early/2016/05/12/jimmun ol.1502343 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/05/12/jimmunol.150234 Material 3.DCSupplemental Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published May 13, 2016, doi:10.4049/jimmunol.1502343 The Journal of Immunology The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells Wilfred Ndifon*,†,‡ and Jonathan Dushoffx Having a large number of sufficiently abundant T cell clones is important for adequate protection against diseases. However, as shown in this paper and elsewhere, between young adulthood and >70 y of age the effective clonal diversity of naive CD4/CD8 T cells found in human blood declines by a factor of >10. (Effective clonal diversity accounts for both the number and the abundance of T cell clones.) The causes of this observation are incompletely understood. A previous study proposed that it might result from the emergence of certain rare, replication-enhancing mutations in T cells. In this paper, we propose an even simpler explanation: that it results from the loss of T cells that have attained replicative senescence (i.e., the Hayflick limit). Stochastic numerical simulations of naive T cell population dynamics, based on experimental parameters, show that the rate of homeostatic ∼ T cell proliferation increases after the age of 60 y because naive T cells collectively approach replicative senescence. This leads to Downloaded from a sharp decline of effective clonal diversity after ∼70 y, in agreement with empirical data. A mathematical analysis predicts that, without an increase in the naive T cell proliferation rate, this decline will occur >50 yr later than empirically observed. These results are consistent with a model in which exhaustion of the proliferative capacity of naive T cells causes a sharp decline of their effective clonal diversity and imply that therapeutic potentiation of thymopoiesis might either prevent or reverse this outcome. The Journal of Immunology, 2016, 196: 000–000. http://www.jimmunol.org/ ndividuals must maintain a large diversity of T cell clones to available TCRs results in severely impaired immune regulation remain protected against a vast array of pathogens to which and the development of colitis in mice (15). I they are constantly exposed (1, 2). The CD8 subset of T cells For human naive T cells, TCR sequence data (9, 11, 16) indicate contributes to the elimination of pathogens by killing infected that their effective clonal diversity (defined as the reciprocal of the cells displaying pathogen-derived Ags on their surface, whereas probability that two randomly chosen T cells belong to the same CD4 T cells are key regulators of these and other immune clone) (17) declines sharply after the age of ∼70 years. Note that responses (3). The magnitude of the T cell response to a newly in contrast to measures of diversity that account only for the encountered Ag depends strongly on the frequencies of naive number of different T cell clones, effective clonal diversity ac- T cell clones that have specificity for that Ag (4, 5). However, counts also for clone frequencies. It is important because the by guest on September 27, 2021 the clonal diversity of naive T cells decreases with age (6–11), magnitude of the T cell response to an Ag depends not only on resulting in the loss of Ag-specific clones. This leads to a failure of whether specific clones are present but also on the frequencies of the immune system to recognize certain Ags, including pathogen such clones as well as how efficiently they are recruited into the derived (12), and a higher probability that recognized Ags will response (4, 5). subsequently acquire mutations that abrogate their recognition The mechanistic basis for the sharp decline of effective clonal (13). Indeed, in certain strains of mice, as little as a 50% reduction diversity observed in old age is incompletely understood. A pos- in T cell diversity is sufficient to create large holes in the space of sible explanation is that the epithelial tissue of the human thymus recognized Ags (14), thus impairing their ability to control certain starts to involute at the age of ∼1 year (18), which causes the infections. Although T cell cross-reactivity can in principle number of new T cells that are subsequently produced by the compensate for such holes, this does not happen in many of the thymus to decrease exponentially with age (9, 11, 19). However, cases that have been studied (2). Thus, an intriguing recent study computer simulations show that neither this exponential decrease showed that reducing clonal diversity by restricting the number of in the rate of thymopoeisis nor the age-associated loss of T cells (20) is sufficient to elicit a dramatic decline of effective clonal diversity (21). An alternative explanation was recently proposed *African Institute for Mathematical Sciences, Muizenberg 7945, Cape Town, (21): that certain rare mutations might arise suddenly in particular South Africa; †African Institute for Mathematical Sciences, Legon, Accra, Ghana; ‡Stellenbosch University, Matieland 7602, Stellenbosch, South Africa; and xDepartment T cells and allow them to outgrow other T cells, thus contributing of Biology, McMaster University, Hamilton, Ontario L8S 4K1, Canada to a sharp decrease in overall effective clonal diversity. ORCID: 0000-0003-0506-4794 (J.D.). In this paper, we propose a simpler explanation, based on the fact Received for publication November 4, 2015. Accepted for publication April 18, 2016. that a differentiated cell can undergo only a limited number of This work was supported by a grant from the Canadian International Development mitotic divisions under normal conditions (22). Specifically, dif- Research Center to the African Institute for Mathematical Sciences. ferentiated diploid cells (e.g., T cells) that are in the resting (or Address correspondence and reprint requests to Dr. Wilfred Ndifon, African Institute quiescent) phase of the cell cycle occasionally enter the prolifer- for Mathematical Sciences, 5-7 Melrose Road, Muizenberg 7945, Cape Town, South ation phase during which they divide. During cell division, the Africa. E-mail address: [email protected] DNA replication machinery found inside each cell copies the The online version of this article contains supplemental material. cell’s chromosomes, except certain base pairs found at chromo- Abbreviations used in this article: resp., respectively; s.e., standard error; TREC, somal ends called telomeres (23). Hence, each cell division TCR excision circle. shortens the telomeres (24, 25) until they reach a critical length Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 (26, 27) that causes the cell to become replicatively senescent. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1502343 2 NAIVE T CELL PROLIFERATION COMPROMISES DIVERSITY (Note that there are other ways in which cells can become se- #2 nucleotide differences from the cluster seed were added to the cluster. nescent without first exhausting their replicative capacity; e.g., see These steps were repeated until all sequences were clustered. We used an Ref. 28). Cells with such critically shortened telomeres are said to adaptation of Simpson’s index applicable to replicate sequence datasets (52) to quantify the effective diversity of all inframe CDR3 amino acid have reached the Hayflick limit (22, 29). Evidence that telomeres sequences corresponding to the cluster seeds. We defined effective diver- shorten as cells proliferate was initially obtained in human fibro- sity as the number of equally abundant sequences that will give a particular blasts (22, 29) and later confirmed in other cell types, including value of Simpson’s index, which is mathematically equivalent to the re- naive T cells (30, 31). Although the enzyme telomerase can in ciprocal of this index (17). principle extend telomeres during cell proliferation (32), its ex- Numerical simulation of T cell population dynamics pression level is low in naive T cells and insufficient to prevent Human naive T cell population dynamics were simulated, starting at the age telomeres from shortening in activated T cells (33). Note that of 20 y and continuing until 100 y. We sampled each T cell clone i from the hematopoietic stem cell aging resulting in telomere attrition (34) geometric distribution G(i)=w (1 2 w)i/(1 2 [1 2 w]S) (21), with bias might also contribute to the emergence of peripheral naive T cells parameter w = 0.01. The maximum size of the T cell population was set to 5 with shorter telomeres. The fact that the emergence of these K =53 10 cells, whereas the total number of possible clones was set to S 3 3 K S T cells in humans is accompanied by the loss of TCR excision =1 10 , as in previous work (21). With these values of and , each clone had an average starting size of K/S = 500, corresponding to an initial circles (TRECs) indicates that homeostatic proliferation is an number of cell divisions of log2(500) = 9.
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