Equipped for Rapid Recall Response T Cells + Human Effector Memory CD4 CCR2 Identifies a Stable Population of

Because T cells act primarily through short-distance interactions, homing receptors can identify colocalizing cells that serve common functions. Expression patterns for multiple chemokine receptors on CD4 + T cells from human blood suggested a hierarchy of receptors that are induced and accumulate during effector/memory cell differentiation. We characterized CD4 + CD45RO + T cells based on expression of two of these receptors, CCR5 and CCR2, the principal subsets being CCR5 2 CCR2 2 ( ∼ 70%), CCR5 + CCR2 2 ( ∼ 25%), and CCR5 + CCR2 + ( ∼ 5%). Relationships among expression of CCR5 and CCR2 and CD62L, and the subsets’ proliferation histories, suggested a pathway of progressive effector/memory differentiation from the CCR5 2 CCR2 2 to CCR5 + CCR2 2 to CCR5 + CCR2 + cells. Sensitivity and rapidity of TCR-mediated activation, TCR signaling, and effector cytokine production by the subsets were consistent with such a pathway. The subsets also showed increasing responsiveness to IL-7, and the CCR5 + CCR2 + cells were CD127 bright and invariably showed the greatest response to tetanus toxoid. CCR5 + CCR2 + cells also expressed the largest repertoire of chemokine receptors and migrated to the greatest number of chemokines. By contrast, the CCR5 + CCR2 2 cells had the greatest percentages of regulatory T cells, activated/cycling cells, and CMV-reactive cells, and were most susceptible to apoptosis. Our results indicate that increasing memory cell differentiation can be uncoupled from susceptibility to death, and is associated with an increase in chemokine 2 , CCR5 + CCR2 2 , and CCR5 + CCR2 + . Our data suggest a pathway of progressive differentiation from CCR5 2 CCR2 2 to CCR5 + CCR2 2 to CCR5 + CCR2 + cells and have implications for understanding the origins, maintenance, and functions of memory subsets. One conclusion suggested by our findings is that to to these features suggest that the + subset contains long-term cells that well equipped for mounting rapid responses to secondary challenges.

[1]  S. Kaech,et al.  Diversity in CD8(+) T cell differentiation. , 2009, Current opinion in immunology.

[2]  J. Geginat,et al.  Brief Definitive Report Identification and Characterization of Il-10/ifn-–producing Effector-like T Cells with Regulatory Function in Human Blood , 2022 .

[3]  P. Marrack,et al.  CD4 memory T cells: what are they and what can they do? , 2009, Seminars in immunology.

[4]  D. Farber.  Biochemical signaling pathways for memory T cell recall. , 2009, Seminars in immunology.

[5]  J. Sprent,et al.  Homeostasis of naive and memory T cells. , 2008, Immunity.

[6]  M. Roederer,et al.  T-cell quality in memory and protection: implications for vaccine design , 2008, Nature Reviews Immunology.

[7]  L. Harrington,et al.  Memory CD4 T cells emerge from effector T-cell progenitors , 2008, Nature.

[8]  H. Dai,et al.  The Role for Monocyte Chemoattractant Protein-1 in the Generation and Function of Memory CD8+ T Cells1 , 2008, The Journal of Immunology.

[9]  R. Zinkernagel,et al.  Long-lived virus-reactive memory T cells generated from purified cytokine-secreting T helper type 1 and type 2 effectors , 2008, The Journal of experimental medicine.

[10]  Augusto Silva,et al.  CCL2 Inhibits the Apoptosis Program Induced by Growth Factor Deprivation, Rescuing Functional T Cells1 , 2007, The Journal of Immunology.

[11]  Inna N. Lavrik,et al.  Life and death in peripheral T cells , 2007, Nature Reviews Immunology.

[12]  H. Zebroski,et al.  Distinct memory CD4+ T-cell subsets mediate immune recognition of Epstein Barr virus nuclear antigen 1 in healthy virus carriers. , 2007, Blood.

[13]  L. Greller,et al.  Convergence of TCR and cytokine signaling leads to FOXO3a phosphorylation and drives the survival of CD4+ central memory T cells , 2007, The Journal of experimental medicine.

[14]  T. Huizinga,et al.  Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells , 2007, European journal of immunology.

[15]  D. Cooper,et al.  CD127+CCR5+CD38+++ CD4+ Th1 Effector Cells Are an Early Component of the Primary Immune Response to Vaccinia Virus and Precede Development of Interleukin-2+ Memory CD4+ T Cells , 2006, Journal of Virology.

[16]  D. Leeser,et al.  Divergent Generation of Heterogeneous Memory CD4 T Cells1 , 2006, The Journal of Immunology.

[17]  T. Gingeras,et al.  CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells , 2006, The Journal of experimental medicine.

[18]  W. Selby,et al.  Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells , 2006, The Journal of experimental medicine.

[19]  M. Battaglia,et al.  Tr1 cells: from discovery to their clinical application. , 2006, Seminars in immunology.

[20]  Arne N. Akbar,et al.  Cytomegalovirus-Specific CD4+ T Cells in Healthy Carriers Are Continuously Driven to Replicative Exhaustion1 , 2005, The Journal of Immunology.

[21]  P. Lipsky,et al.  Stepwise Differentiation of CD4 Memory T Cells Defined by Expression of CCR7 and CD271 , 2005, The Journal of Immunology.

[22]  D. Farber,et al.  Novel phenotypes and migratory properties distinguish memory CD4 T cell subsets in lymphoid and lung tissue , 2005, European journal of immunology.

[23]  R. D. Hatton,et al.  Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages , 2005, Nature Immunology.

[24]  E. Remmerswaal,et al.  IL-7 receptor alpha chain expression distinguishes functional subsets of virus-specific human CD8+ T cells. , 2005, Blood.

[25]  Louis J. Picker,et al.  Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects , 2005, The Journal of experimental medicine.

[26]  Q. Jiang,et al.  Cell biology of IL-7, a key lymphotrophin. , 2005, Cytokine & growth factor reviews.

[27]  Leo Lefrançois,et al.  Initial T cell frequency dictates memory CD8+ T cell lineage commitment , 2005, Nature Immunology.

[28]  Antonio Lanzavecchia,et al.  Understanding the generation and function of memory T cell subsets. , 2005, Current opinion in immunology.

[29]  R. Rabin,et al.  Characterization of subsets of CD4+ memory T cells reveals early branched pathways of T cell differentiation in humans , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[30]  T. Nomura,et al.  Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. , 2004, International immunology.

[31]  R. Boyd,et al.  Strategies to enhance T-cell reconstitution in immunocompromised patients , 2004, Nature Reviews Immunology.

[32]  P. Scott,et al.  Central memory T cells mediate long-term immunity to Leishmania major in the absence of persistent parasites , 2004, Nature Medicine.

[33]  Antonio Lanzavecchia,et al.  Chemokine Receptor Expression Identifies Pre–T Helper (Th)1, Pre–Th2, and Nonpolarized Cells among Human CD4+ Central Memory T Cells , 2004, The Journal of experimental medicine.

[34]  A. Singer,et al.  Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. , 2004, Immunity.

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

[36]  Alan D. Roberts,et al.  Cutting Edge: Effector Memory CD8+ T Cells Play a Prominent Role in Recall Responses to Secondary Viral Infection in the Lung1 , 2004, The Journal of Immunology.

[37]  D. Farber,et al.  Memory T Cells in Transplantation: Generation, Function, and Potential Role in Rejection , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[38]  S. Sakaguchi.  Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. , 2004, Annual review of immunology.

[39]  Antonio Lanzavecchia,et al.  Central memory and effector memory T cell subsets: function, generation, and maintenance. , 2004, Annual review of immunology.

[40]  Mario A. Ostrowski,et al.  HIV-1-Specific Memory CD4+ T Cells Are Phenotypically Less Mature Than Cytomegalovirus-Specific Memory CD4+ T Cells 1 , 2004, The Journal of Immunology.

[41]  J. Sprent,et al.  T cell memory. , 2003, Annual review of immunology.

[42]  Andrew J. McMichael,et al.  Characterization of the CD4+ T Cell Response to Epstein-Barr Virus during Primary and Persistent Infection , 2003, The Journal of experimental medicine.

[43]  I. Charo,et al.  Chemokine Receptor 2 (CCR2) in Atherosclerosis, Infectious Diseases, and Regulation of T‐Cell Polarization , 2003, Microcirculation.

[44]  J. Corbeil,et al.  Polyclonal proliferation and apoptosis of CCR5+ T lymphocytes during primary human immunodeficiency virus type 1 infection: regulation by interleukin (IL)-2, IL-15, and Bcl-2. , 2003, The Journal of infectious diseases.

[45]  Rustom Antia,et al.  Lineage relationship and protective immunity of memory CD8 T cell subsets , 2003, Nature Immunology.

[46]  R. Lempicki,et al.  Cutting Edge: L-Selectin (CD62L) Expression Distinguishes Small Resting Memory CD4+ T Cells That Preferentially Respond to Recall Antigen , 2003, The Journal of Immunology.

[47]  U. V. von Andrian,et al.  CD4 Effector T Cell Subsets in the Response to Influenza , 2002, The Journal of experimental medicine.

[48]  Daniel C. Douek,et al.  Distinct lineages of TH1 cells have differential capacities for memory cell generation in vivo , 2002, Nature Immunology.

[49]  N. Tsuyama,et al.  Memory Functions and Death Proneness in Three CD4+CD45RO+ Human T Cell Subsets1 , 2002, The Journal of Immunology.

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

[51]  F. Ronchese,et al.  Differential T Cell Function and Fate in Lymph Node and Nonlymphoid Tissues , 2002, The Journal of experimental medicine.

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

[53]  Alan D. Roberts,et al.  Protection from Respiratory Virus Infections Can Be Mediated by Antigen-Specific Cd4+ T Cells That Persist in the Lungs , 2001, The Journal of experimental medicine.

[54]  L. Lefrançois,et al.  Preferential Localization of Effector Memory Cells in Nonlymphoid Tissue , 2001, Science.

[55]  A. Khoruts,et al.  Visualizing the generation of memory CD4 T cells in the whole body , 2001, Nature.

[56]  D. Cooper,et al.  Increased turnover of CCR5+ and redistribution of CCR5- CD4 T lymphocytes during primary human immunodeficiency virus type 1 infection. , 2001, The Journal of infectious diseases.

[57]  M. Roederer,et al.  11-color, 13-parameter flow cytometry: Identification of human naive T cells by phenotype, function, and T-cell receptor diversity , 2001, Nature Medicine.

[58]  A. Clark.  Post-transcriptional regulation of pro-inflammatory gene expression , 2000, Arthritis research.

[59]  V. Maino,et al.  Frequencies of memory T cells specific for varicella-zoster virus, herpes simplex virus, and cytomegalovirus by intracellular detection of cytokine expression. , 2000, The Journal of infectious diseases.

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

[61]  E. Wolf,et al.  CCR7 Coordinates the Primary Immune Response by Establishing Functional Microenvironments in Secondary Lymphoid Organs , 1999, Cell.

[62]  N. Thompson,et al.  CD4+CD45RA+ and CD4+CD45RO+ T cells differ in their TCR‐associated signaling responses , 1999, European journal of immunology.

[63]  H. Etlinger,et al.  the Journal of Immunology , 2006 .

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

[65]  E. Ingulli,et al.  Visualization of specific B and T lymphocyte interactions in the lymph node. , 1998, Science.

[66]  Marc Parmentier,et al.  A Dual-Tropic Primary HIV-1 Isolate That Uses Fusin and the β-Chemokine Receptors CKR-5, CKR-3, and CKR-2b as Fusion Cofactors , 1996, Cell.

[67]  C. Mackay,et al.  Expression of monocyte chemoattractant protein‐1 and interleukin‐8 receptors on subsets of T cells: correlation with transendothelial chemotactic potential , 1996, European journal of immunology.

[68]  M. Roederer,et al.  Heterogeneous calcium flux in peripheral T cell subsets revealed by five-color flow cytometry using log-ratio circuitry. , 1995, Cytometry.

[69]  R. Brezinschek,et al.  Phenotypic characterization of CD4+ T cells that exhibit a transendothelial migratory capacity. , 1995, Journal of immunology.

[70]  K. Ley,et al.  Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice. , 1994, Immunity.

[71]  T. Springer,et al.  Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[72]  T. Springer.  Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm , 1994, Cell.

[73]  L. Picker,et al.  Control of lymphocyte recirculation in man. I. Differential regulation of the peripheral lymph node homing receptor L-selectin on T cells during the virgin to memory cell transition. , 1993, Journal of immunology.

[74]  G. Pantaleo,et al.  Functional and phenotypic characterization of tetanus toxoid-specific human CD4+ T cells following re-immunization. , 2007, European journal of immunology.

[75]  H. Stein,et al.  Analysis of FOXP3 protein expression in human CD4(+)CD25(+) regulatory T cells at the single-cell level. , 2006, European journal of immunology.

[76]  P. Krammer,et al.  In contrast to effector T cells, CD4+CD25+FoxP3+ regulatory T cells are highly susceptible to CD95 ligand- but not to TCR-mediated cell death. , 2005, Journal of immunology.

[77]  M. Parmentier,et al.  CCR5 and HIV infection. , 2002, Receptors & channels.

[78]  R. Zinkernagel,et al.  CD4 1 T Cell Subsets during Virus Infection: Protective Capacity Depends on Effector Cytokine Secretion and on Migratory Capability , 2000 .