Quantification of T‐cell dynamics: from telomeres to DNA labeling

Summary:  Immunology has traditionally been a qualitative science describing the cellular and molecular components of the immune system and their functions. Only quite recently have new experimental techniques paved the way for a more quantitative approach of immunology. Lymphocyte telomere lengths have been measured to get insights into the proliferation rate of different lymphocyte subsets, T‐cell receptor excision circles have been used to quantify the daily output of new T cells from the thymus, and bromodeoxyuridine and stable isotope labeling have been applied to measure proliferation and death rates of naive and memory lymphocytes. A common problem of the above techniques is the translation of the resulting data into relevant parameters, such as the typical division and death rate of the different lymphocyte populations. Theoretical immunology has contributed significantly to the interpretation of such quantitative experimental data, thereby resolving diverse controversies and, most importantly, has suggested novel experiments, allowing for more conclusive and quantitative interpretations. In this article, we review a variety of different models that have been used to interpret data on lymphocyte kinetics in healthy human subjects and discuss their contributions and limitations.

[1]  M. Hellerstein,et al.  Mass isotopomer distribution analysis: a technique for measuring biosynthesis and turnover of polymers. , 1992, The American journal of physiology.

[2]  Becca Asquith,et al.  Measurement and modeling of human T cell kinetics. , 2003, European journal of immunology.

[3]  R. Lempicki,et al.  Impact of HIV-1 infection and highly active antiretroviral therapy on the kinetics of CD4+ and CD8+ T cell turnover in HIV-infected patients. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Julia A. Metcalf,et al.  Naïve T-Cell Dynamics in Human Immunodeficiency Virus Type 1 Infection: Effects of Highly Active Antiretroviral Therapy Provide Insights into the Mechanisms of Naïve T-Cell Depletion , 2006, Journal of Virology.

[5]  Ronald B. Herberman,et al.  T Cell Turnover in SIV Infection , 1999 .

[6]  D. Tough,et al.  Direct Measurement of T Cell Subset Kinetics In Vivo in Elderly Men and Women1 , 2004, The Journal of Immunology.

[7]  G. Pantaleo,et al.  De novo T-cell generation in patients at different ages and stages of HIV-1 disease. , 2004, Blood.

[8]  Douglas A. Hosack,et al.  Induction of prolonged survival of CD4+ T lymphocytes by intermittent IL-2 therapy in HIV-infected patients. , 2005, The Journal of clinical investigation.

[9]  J. McCune,et al.  Multiparameter evaluation of human thymic function: interpretations and caveats. , 2005, Clinical immunology.

[10]  S. Steinberg,et al.  Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. , 1995, The New England journal of medicine.

[11]  B. Rocha,et al.  Accumulation of bromodeoxyuridine‐labeled cells in central and peripheral lymphoid organs: minimal estimates of prodution and turnover rates of mature lymphocytes , 1990, European journal of immunology.

[12]  R. Collins,et al.  Assessment of thymic output in adults after haematopoietic stemcell transplantation and prediction of T-cell reconstitution , 2000, The Lancet.

[13]  Alan S. Perelson,et al.  Quantification of Cell Turnover Kinetics Using 5-Bromo-2′-deoxyuridine1 , 2000, The Journal of Immunology.

[14]  M. Cooper,et al.  Thymic function can be accurately monitored by the level of recent T cell emigrants in the circulation. , 1998, Immunity.

[15]  C. Mackall,et al.  Thymic-independent T cell regeneration occurs via antigen-driven expansion of peripheral T cells resulting in a repertoire that is limited in diversity and prone to skewing. , 1996, Journal of immunology.

[16]  J. Mittler,et al.  Modeling T-cell proliferation: an investigation of the consequences of the Hayflick limit. , 1997, Journal of theoretical biology.

[17]  Alan S. Perelson,et al.  Estimating division and death rates from CFSE data , 2005 .

[18]  Rustom Antia,et al.  Quantifying cell turnover using CFSE data. , 2005, Journal of immunological methods.

[19]  C. Bangham,et al.  Review. An introduction to lymphocyte and viral dynamics: the power and limitations of mathematical analysis , 2003, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[20]  Alan S. Perelson,et al.  Dynamics of T Cells and TCR Excision Circles Differ After Treatment of Acute and Chronic HIV Infection1 2 , 2002, The Journal of Immunology.

[21]  Alan S. Perelson,et al.  In vivo dynamics of T cell activation, proliferation, and death in HIV-1 infection: Why are CD4+ but not CD8+ T cells depleted? , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  A. Burny,et al.  Increased cell proliferation, but not reduced cell death, induces lymphocytosis in bovine leukemia virus-infected sheep , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[23]  A. McLean,et al.  In vivo estimates of division and death rates of human T lymphocytes. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Philip D. Hodgkin,et al.  A cellular calculus for signal integration by T cells , 2000, Nature Immunology.

[25]  J. McCune,et al.  Measurement in vivo of proliferation rates of slow turnover cells by 2H2O labeling of the deoxyribose moiety of DNA , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[26]  D. Tough,et al.  Rapid Turnover of Effector–Memory CD4+ T Cells in Healthy Humans , 2004, The Journal of experimental medicine.

[27]  F Miedema,et al.  T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART). , 2000, Blood.

[28]  Alan S. Perelson,et al.  Turnover Rates of B Cells, T Cells, and NK Cells in Simian Immunodeficiency Virus-Infected and Uninfected Rhesus Macaques1 , 2003, The Journal of Immunology.

[29]  Louis J. Picker,et al.  Changes in thymic function with age and during the treatment of HIV infection , 1998, Nature.

[30]  C. Mackall,et al.  Pathways of T‐cell regeneration in mice and humans: implications for bone marrow transplantation and immmunotherapy , 1997, Immunological reviews.

[31]  Alan S. Perelson,et al.  Turnover of CD4+ and CD8+ T Lymphocytes in HIV-1 Infection as Measured by Ki-67 Antigen , 1998, The Journal of experimental medicine.

[32]  B. Leber,et al.  Telomerase activity in normal leukocytes and in hematologic malignancies. , 1995, Blood.

[33]  Steven G. Deeks,et al.  Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans , 1999, Nature Medicine.

[34]  V A Zakian,et al.  Structure and function of telomeres. , 1989, Annual review of genetics.

[35]  Rob J. de Boer,et al.  Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection , 2000, Nature Medicine.

[36]  Becca Asquith,et al.  Lymphocyte kinetics: the interpretation of labelling data. , 2002, Trends in immunology.

[37]  Bas E Dutilh,et al.  Decline in excision circles requires homeostatic renewal or homeostatic death of naive T cells. , 2003, Journal of theoretical biology.

[38]  R Hoh,et al.  Factors influencing T-cell turnover in HIV-1-seropositive patients. , 2000, The Journal of clinical investigation.

[39]  L. Hayflick Antecedents of cell aging research , 1989, Experimental Gerontology.

[40]  M. Hellerstein,et al.  Measurement of cell proliferation by labeling of DNA with stable isotope-labeled glucose: studies in vitro, in animals, and in humans. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[41]  C B Harley,et al.  Telomere length predicts replicative capacity of human fibroblasts. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Alan S. Perelson,et al.  Estimating average cellular turnover from 5–bromo–2'–deoxyuridine (BrdU) measurements , 2003, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[43]  Boris Barbour,et al.  Functional antigen-independent synapses formed between T cells and dendritic cells , 2001, Nature Immunology.

[44]  A. Noest,et al.  T cell renewal rates, telomerase, and telomere length shortening. , 1998, Journal of immunology.

[45]  C. Harley,et al.  Telomeres shorten during ageing of human fibroblasts , 1990, Nature.

[46]  J. Sprent,et al.  Turnover of Naive-and Memory-phenotype T Cells , 1994 .

[47]  Rob J. de Boer,et al.  Thymic output: a bad TREC record , 2003, Nature Immunology.

[48]  R. May Uses and Abuses of Mathematics in Biology , 2004, Science.

[49]  Alan S. Perelson,et al.  Modeling deuterated glucose labeling of T-lymphocytes , 2002, Bulletin of mathematical biology.

[50]  A S Perelson,et al.  Rapid turnover of T lymphocytes in SIV-infected rhesus macaques. , 1998, Science.

[51]  Richard A. Lempicki,et al.  Identification of Dynamically Distinct Subpopulations of T Lymphocytes That Are Differentially Affected by HIV , 2001, The Journal of experimental medicine.

[52]  B L Levine,et al.  Human naive and memory T lymphocytes differ in telomeric length and replicative potential. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[53]  R. J. Boer Estimating the role of thymic output in HIV infection. , 2006 .

[54]  Marc K Hellerstein,et al.  Subpopulations of long-lived and short-lived T cells in advanced HIV-1 infection. , 2003, The Journal of clinical investigation.

[55]  Alan S. Perelson,et al.  Increased Turnover of T Lymphocytes in HIV-1 Infection and Its Reduction by Antiretroviral Therapy , 2001, The Journal of experimental medicine.

[56]  F. Miedema,et al.  Establishment of the CD4+ T-cell pool in healthy children and untreated children infected with HIV-1. , 2004, Blood.

[57]  R. Hodes,et al.  Regulation of telomere length and telomerase in T and B cells: a mechanism for maintaining replicative potential. , 1998, Immunity.

[58]  C. Mackall,et al.  Thymic aging and T‐cell regeneration , 1997, Immunological reviews.

[59]  Elissa K. Deenick,et al.  Stochastic Model of T Cell Proliferation: A Calculus Revealing IL-2 Regulation of Precursor Frequencies, Cell Cycle Time, and Survival1 , 2003, The Journal of Immunology.

[60]  A. McLean,et al.  Lifespan of human lymphocyte subsets defined by CD45 isoforms , 1992, Nature.