Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines.

Four human CD8+ T-cell subsets, naive (CCR7+CD45RA+), central memory (TCM, CCR7+CD45RA-), effector memory (TEM, CCR7-CD45RA-), and CD45RA+ effector memory cells (TEMRA, CCR7-CD45RA+) were compared for their capacity to proliferate and differentiate in response to antigen or homeostatic cytokines. Cytokine responsiveness and interleukin-15 receptor expression were low in naive T cells and progressively increased from TCM to TEM and TEMRA. In contrast, the capacity to accumulate in response to T-cell receptor (TCR) or cytokine stimulation showed a reciprocal pattern and was associated with resistance to cell death and Bcl-2 expression. Whereas all TCR-stimulated cells acquired a CD45RA-CCR7- phenotype, cytokine-stimulated cells maintained their phenotype with the exception of TCM cells, which expressed CCR7, CD45RA, and perforin in various combinations. Single CD8+ TCM cells, but not TEM cells, could be expanded with cytokines, and the obtained clones displayed several distinct phenotypes, suggesting that TCM cells are heterogeneous. Consistently, CCR4 expression in the CD8+ TCM pool discriminated CCR4+ type 2 polarized cells (Tc2) and CCR4-CTL precursors. Finally, ex vivo bromodeoxyuridine (BrdU) incorporation experiments revealed that memory subsets have different in vivo proliferation rates, with CCR4-TCM having the highest turnover and TEMRA the lowest. These results show that human CD8+ memory T-cell subsets have different proliferation and differentiation potentials in vitro and in vivo. Furthermore, they suggest that TEMRA cells are generated from a TCM subset upon homeostatic proliferation in the absence of antigen.

[1]  J. Waldenström Benign monoclonal gammapathy. , 2009, Acta medica Scandinavica.

[2]  J. Sprent,et al.  Interleukin 15 Controls both Proliferation and Survival of a Subset of Memory-Phenotype CD8+ T Cells , 2002, The Journal of experimental medicine.

[3]  R. Zamoyska,et al.  TCR and IL-7 Receptor Signals Can Operate Independently or Synergize to Promote Lymphopenia-Induced Expansion of Naive T Cells1 , 2002, The Journal of Immunology.

[4]  M. Salmon,et al.  Epstein-Barr virus-specific CD8(+) T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential. , 2002, Blood.

[5]  C. Benoist,et al.  Cytokine Requirements for Acute and Basal Homeostatic Proliferation of Naive and Memory CD8+ T Cells , 2002, The Journal of experimental medicine.

[6]  J. Sprent,et al.  Overexpression of Interleukin (IL)-7 Leads to IL-15–independent Generation of Memory Phenotype CD8+ T Cells , 2002, The Journal of experimental medicine.

[7]  J. Sprent,et al.  Interleukin (IL)-15 and IL-7 Jointly Regulate Homeostatic Proliferation of Memory Phenotype CD8+ Cells but Are Not Required for Memory Phenotype CD4+ Cells , 2002, The Journal of experimental medicine.

[8]  A. Rickinson,et al.  Epitope-specific Evolution of Human CD8+ T Cell Responses from Primary to Persistent Phases of Epstein-Barr Virus Infection , 2002, The Journal of experimental medicine.

[9]  D. Richman,et al.  Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections , 2002, Nature Medicine.

[10]  Danila Valmori,et al.  Thymic Selection Generates a Large T Cell Pool Recognizing a Self-Peptide in Humans , 2002, The Journal of experimental medicine.

[11]  F. Sallusto,et al.  Cytokine-driven proliferation and differentiation of human naïve, central memory and effector memory CD4+ T cells. , 2003, Pathologie-biologie.

[12]  T. Blankenstein,et al.  Generation of Tumor-associated Cytotoxic T Lymphocytes Requires Interleukin 4 from CD8+ T Cells , 2001, The Journal of experimental medicine.

[13]  F. Sallusto,et al.  Cytokine-driven Proliferation and Differentiation of Human Naive, Central Memory, and Effector Memory CD4+ T Cells , 2001, The Journal of experimental medicine.

[14]  Meng-tse Wu,et al.  Cutting Edge: CCR4 Mediates Antigen-Primed T Cell Binding to Activated Dendritic Cells , 2001, The Journal of Immunology.

[15]  E. Kunkel,et al.  Rules of chemokine receptor association with T cell polarization in vivo. , 2001, The Journal of clinical investigation.

[16]  T. Fry,et al.  Interleukin-7: master regulator of peripheral T-cell homeostasis? , 2001, Trends in immunology.

[17]  A. Iellem,et al.  Unique Chemotactic Response Profile and Specific Expression of Chemokine Receptors Ccr4 and Ccr8 by Cd4+Cd25+ Regulatory T Cells , 2001, The Journal of experimental medicine.

[18]  Raymond M. Welsh,et al.  Attrition of Bystander CD8 T Cells during Virus-Induced T-Cell and Interferon Responses , 2001, Journal of Virology.

[19]  P. Moss,et al.  Memory T Cells Constitute a Subset of the Human CD8+CD45RA+ Pool with Distinct Phenotypic and Migratory Characteristics1 , 2001, The Journal of Immunology.

[20]  S. Rowland-Jones,et al.  Skewed maturation of memory HIV-specific CD8 T lymphocytes , 2001, Nature.

[21]  N. Rufer,et al.  Human memory T cells: lessons from stem cell transplantation. , 2001, Trends in immunology.

[22]  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.

[23]  S. Jameson,et al.  Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo , 2000, Nature Immunology.

[24]  L. Bogatzki,et al.  Naive T Cells Transiently Acquire a Memory-like Phenotype during Homeostasis-Driven Proliferation , 2000, The Journal of experimental medicine.

[25]  R. Ahmed,et al.  Cutting Edge: Naive T Cells Masquerading as Memory Cells , 2000, The Journal of Immunology.

[26]  P. Marrack,et al.  Control of homeostasis of CD8+ memory T cells by opposing cytokines. , 2000, Science.

[27]  F. Chen,et al.  Potent induction of long-term CD8+ T cell memory by short-term IL-4 exposure during T cell receptor stimulation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[28]  David Steven Scott,et al.  Regulation of the G1 phase of the mammalian cell cycle , 2000, Cell Research.

[29]  Matthew G. Vander Heiden,et al.  Bcl-2 proteins: regulators of apoptosis or of mitochondrial homeostasis? , 1999, Nature Cell Biology.

[30]  J. Altman,et al.  Persistence of memory CD8 T cells in MHC class I-deficient mice. , 1999, Science.

[31]  H. Eisen,et al.  Functional differences between memory and naive CD8 T cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[32]  C. Irwin,et al.  Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28- cytotoxic effector clones. , 1999, International immunology.

[33]  K. Brduscha-Riem,et al.  Naïve cytotoxic T lymphocytes spontaneously acquire effector function in lymphocytopenic recipients: A pitfall for T cell memory studies? , 1999, European journal of immunology.

[34]  W. Ouyang,et al.  Induction of interferon‐γ production in Th1 CD4+ T cells: evidence for two distinct pathways for promoter activation , 1999 .

[35]  D. Kemeny,et al.  CD8+ T cells in atopic disease. , 1998, Current opinion in immunology.

[36]  A. Mantovani,et al.  Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. , 1998, Journal of immunology.

[37]  T. Dassopoulos,et al.  IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. , 1998, Immunity.

[38]  J. Sprent,et al.  Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. , 1998, Immunity.

[39]  C. Mackay,et al.  Flexible Programs of Chemokine Receptor Expression on Human Polarized T Helper 1 and 2 Lymphocytes , 1998, The Journal of experimental medicine.

[40]  B. Hock,et al.  Human dendritic cells express functional interleukin-7. , 1998, Immunobiology.

[41]  M. Rep,et al.  Phenotypic and Functional Separation of Memory and Effector Human CD8+ T Cells , 1997, The Journal of experimental medicine.

[42]  A. Berns,et al.  Peripheral T Cell Survival Requires Continual Ligation of the T Cell Receptor to Major Histocompatibility Complex–Encoded Molecules , 1997, The Journal of experimental medicine.

[43]  F. Lemonnier,et al.  Differential requirements for survival and proliferation of CD8 naïve or memory T cells. , 1997, Science.

[44]  A. Enk,et al.  Induction of IL-15 messenger RNA and protein in human blood-derived dendritic cells: a role for IL-15 in attraction of T cells. , 1997, Journal of immunology.

[45]  H. Kanegane,et al.  Activation of naive and memory T cells by interleukin-15. , 1996, Blood.

[46]  J. Sprent,et al.  Induction of Bystander T Cell Proliferation by Viruses and Type I Interferon in Vivo , 1996, Science.

[47]  S. Abrignani,et al.  Human naive T cells activated by cytokines differentiate into a split phenotype with functional features intermediate between naive and memory T cells. , 1995, International immunology.

[48]  P. Pileri,et al.  Antigen-independent activation of naive and memory resting T cells by a cytokine combination , 1994, The Journal of experimental medicine.

[49]  F. Erard,et al.  Non-cytotoxic, IL-4, IL-5, IL-10 producing CD8+ T cells: their activation and effector functions. , 1994, Current opinion in immunology.

[50]  A. B. Lyons,et al.  Determination of lymphocyte division by flow cytometry. , 1994, Journal of immunological methods.

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

[52]  F. Sallusto,et al.  Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha , 1994, The Journal of experimental medicine.

[53]  D N Posnett,et al.  Clonal populations of T cells in normal elderly humans: the T cell equivalent to "benign monoclonal gammapathy" [published erratum appears in J Exp Med 1994 Mar 1;179(3):1077] , 1994, The Journal of experimental medicine.

[54]  M. Salmon,et al.  The significance of low bcl-2 expression by CD45RO T cells in normal individuals and patients with acute viral infections. The role of apoptosis in T cell memory , 1993, The Journal of experimental medicine.

[55]  L. Lanier,et al.  CD28- T lymphocytes. Antigenic and functional properties. , 1993, Journal of immunology.

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

[57]  R. Armitage,et al.  Human IL-7: a novel T cell growth factor. , 1989, Journal of immunology.

[58]  M. Prlic,et al.  Multiple Choices: Regulation of Memory CD8 T Cell Generation and Homeostasis by Interleukin (IL)-7 and IL-15 , 2002 .

[59]  R. Grant,et al.  Increased production of IL-7 accompanies HIV-1–mediated T-cell depletion: implications for T-cell homeostasis , 2001, Nature Medicine.

[60]  B. Rocha,et al.  Population biology of lymphocytes: the flight for survival. , 2000, Annual review of immunology.

[61]  F. Sallusto,et al.  Two subsets of memory T lymphocytes with distinct homing potentials and effector functions , 1999, Nature.