Four Functionally Distinct Populations of Human Effector-Memory CD8+ T Lymphocytes

Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research-Lausanne Branch, University Hospital of Lausanne, Lausanne, Switzerland.
The Journal of Immunology (Impact Factor: 4.92). 05/2007; 178(7):4112-9. DOI: 10.4049/jimmunol.178.7.4112
Source: PubMed


In humans, the pathways of memory and effector T cell differentiation remain poorly defined. We have dissected the functional properties of ex vivo effector-memory (EM) CD45RA-CCR7- T lymphocytes present within the circulating CD8+ T cell pool of healthy individuals. Our studies show that EM T cells are heterogeneous and are subdivided based on differential CD27 and CD28 expression into four subsets. EM(1) (CD27+CD28+) and EM(4) (CD27-CD28+) T cells express low levels of effector mediators such as granzyme B and perforin and high levels of CD127/IL-7Ralpha. EM(1) cells also have a relatively short replicative history and display strong ex vivo telomerase activity. Therefore, these cells are closely related to central-memory (CD45RA-CCR7+) cells. In contrast, EM(2) (CD27+CD28-) and EM(3) (CD27-CD28-) cells express mediators characteristic of effector cells, whereby EM(3) cells display stronger ex vivo cytolytic activity and have experienced larger numbers of cell divisions, thus resembling differentiated effector (CD45RA+CCR7-) cells. These data indicate that progressive up-regulation of cytolytic activity and stepwise loss of CCR7, CD28, and CD27 both characterize CD8+ T cell differentiation. Finally, memory CD8+ T cells not only include central-memory cells but also EM(1) cells, which differ in CCR7 expression and may therefore confer memory functions in lymphoid and peripheral tissues, respectively.

Download full-text


Available from: Mikael J Pittet
    • "TEM mainly produce interferon-γ , promoting antigen presentation of APCs and cytotoxic immune responses (Willinger et al., 2005). TEMRA are the most terminally differentiated memory cells characterized by immediate effector function, short telomers and markers of senescence with low proliferative and functional capacity (Geginat et al., 2003; Sallusto et al., 2004; Romero et al., 2007; Henson & Akbar, 2009). The mentioned phenotypic, functional and gene expression profiles suggest a linear differential relationship between the memory cell subsets: TN → TCM → TEM → TEMRA. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The migration of immune cells from peripheral immune organs into the central nervous system (CNS) through the blood–brain barrier (BBB) is a tightly regulated process. The complex interplay between cells of the BBB and immune cells coordinates cell migration as a part of normal immune surveillance while its dysregulation is critically involved in the pathogenesis of various CNS diseases. To develop tools for a deeper understanding of distribution and migratory pattern of immune cells regulated by the BBB, we made use of a mathematical modelling approach derived from Markov chain theory. We present a data-driven model using a derivation of kinetic differential equations from a particle game. According to the theory of gases, these equations allow one to predict the mean behaviour of a large class of cells by modelling cell–cell interactions. We used this model to assess the distribution of naive, central memory and effector memory T lymphocytes in the peripheral blood and cerebrospinal fluid. Our model allows us to evaluate the impact of activation status, migratory capacity and cell death for cell distribution in the peripheral blood and the CNS.
    No preview · Article · Oct 2015 · Mathematical Medicine and Biology
  • Source
    • "CCR7, CD45RA), or costimulatory molecules (e.g. CD27, CD28) [9]–[11]. Naive CD8+ T cells express high molecular weight isoforms of leukocyte common antigen CD45RA, CD28 and CCR7, a lymph-node-homing chemokine receptor. "
    [Show abstract] [Hide abstract]
    ABSTRACT: CD8(+) T cells play important roles in anti-tumor immunity but distribution profile or functional characteristics of effector memory subsets during tumor progression are unclear. We found that, in oral squamous carcinoma patients, circulating CD8(+) T cell pools skewed toward effector memory subsets with the distribution frequency of CCR7(-)CD45RA(-)CD8(+) T cells and CCR7(-) CD45RA(+)CD8(+) T cells negatively correlated with each other. A significantly higher frequency of CD127(lo) CCR7(-)CD45RA(-)CD8(+) T cells or CCR7(-)CD45RA(+)CD8(+) T cells among total CD8(+) T cells was found in peripheral blood or tumor infiltrating lymphocytes, but not in regional lymph nodes. The CD127(hi) CCR7(-)CD45RA(-)CD8(+) T cells or CCR7(-)CD45RA(+)CD8(+) T cells maintained significantly higher IFN-γ, IL-2 productivity and ex vivo proliferative capacity, while the CD127(lo) CCR7(-)CD45RA(-)CD8(+) T cells or CCR7(-)CD45RA(+)CD8(+) T cells exhibited higher granzyme B productivity and susceptibility to activation induced cell death. A higher ratio of CCR7(-)CD45RA(+)CD8(+) T cells to CCR7(-)CD45RA(-)CD8(+) T cells was associated with advanced cancer staging and poor differentiation of tumor cells. Therefore, the CD127(lo) CCR7(-)CD45RA(-)CD8(+) T cells and CCR7(-)CD45RA(+)CD8(+) T cells are functionally similar CD8(+) T cell subsets which exhibit late differentiated effector phenotypes and the shift of peripheral CD8(+) effector memory balance toward CCR7(-)CD45RA(+)CD8(+) T cells is associated with OSCC progression.
    Full-text · Article · Jan 2014 · PLoS ONE
  • Source
    • "Although mass cytometry is far from a comprehensive ‘proteomics’ method, extending cellular analysis into 40 dimensions means that each cell can be parsed into one of 240 (∼1 trillion) possible bins, allowing cells to be classified in unprecedented detail. It also means that a wide variety of T-cell markers can be can be assessed simultaneously providing a view of the overall diversity of a sample of cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adaptive immune responses often begin with the formation of a molecular complex between a T-cell receptor (TCR) and a peptide antigen bound to a major histocompatibility complex (MHC) molecule. These complexes are highly variable, however, due to the polymorphism of MHC genes, the random, inexact recombination of TCR gene segments, and the vast array of possible self and pathogen peptide antigens. As a result, it has been very difficult to comprehensively study the TCR repertoire or identify and track more than a few antigen-specific T cells in mice or humans. For mouse studies, this had led to a reliance on model antigens and TCR transgenes. The study of limited human clinical samples, in contrast, requires techniques that can simultaneously survey TCR phenotype and function, and TCR reactivity to many T-cell epitopes. Thanks to recent advances in single-cell and cytometry methodologies, as well as high-throughput sequencing of the TCR repertoire, we now have or will soon have the tools needed to comprehensively analyze T-cell responses in health and disease.
    Preview · Article · Jan 2014 · Nature Biotechnology
Show more