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,
90 Reads
  • 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.
    PLoS ONE 01/2014; 9(1):e85521. DOI:10.1371/journal.pone.0085521 · 3.23 Impact Factor
  • 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.
    Nature Biotechnology 01/2014; 32(2). DOI:10.1038/nbt.2783 · 41.51 Impact Factor
    • "Recent studies have observed a high degree of heterogeneity in the effector memory (EM; CD45RA-CCR7-) subset with differential expression of CD28 and CD27 molecules. Thus Romero et al25 proposed the categorization of this section as well, the resultant being 4 phenotypically distinct subpopulations called EM1(CD27+CD28+), EM2(CD27+CD28-), EM3(CD27-CD28-) and EM4(CD27-CD28+). Of these, three subsets are functionally distinct, with EM1 being memory like, EM2 exhibiting partial replicative history and effector functions and EM3 being effector like. "
    [Show abstract] [Hide abstract]
    ABSTRACT: HIV continues to be a major health problem worldwide even today. Owing to the intricate nature of its interactions with the immune system, HIV has remained an enigma that cleverly utilizes the host machinery to survive. Its ability to evade the host immune system, at both levels, innate and adaptive, allows the pathogen to replicate and transmit from one host to another. It has been shown that HIV has multipronged effects especially on the adaptive immunity, with CD4+ T cells being the worst affected T cell populations. Various analyses have revealed that the exposure to HIV results in clonal expansion and excessive activation of the immune system. Also, an abnormal process of differentiation has been observed suggestive of an alteration and blocks in the maturation of various T cell subsets. Additionally, HIV has shown to accelerate immunosenescence and exhaustion of the overtly activated T cells. Apart from causing phenotypic changes, HIV has adverse effects on the functional aspect of the immune system, with evidences implicating it in the loss of the capacity of T cells to secrete various antiviral cytokines and chemokines. However, there continues to be many aspects of the immunopathogenesis of HIV that are still unknown and thus require further research to convert the malaise of HIV into a manageable epidemic.
    The Indian Journal of Medical Research 11/2013; 138(5):682-99. · 1.40 Impact Factor
Show more