René A. W. van Lier

CD27 is required for generation and long-term maintenance of T cell immunity

The Traf-linked tumor necrosis factor receptor family member CD27 is known as a T cell costimulatory molecule. We generated CD27−/− mice and found that CD27 makes essential contributions to mature CD4+ and CD8+ T cell function: CD27 supported antigen-specific expansion (but not effector cell maturation) of naïve T cells, independent of the cell cycle–promoting activities of CD28 and interleukin 2. Primary CD4+ and CD8+ T cell responses to influenza virus were impaired in CD27−/− mice. Effects of deleting the gene encoding CD27 were most profound on T cell memory, reflected by delayed response kinetics and reduction of CD8+ virus-specific T cell numbers to the level seen in the primary response. This demonstrates the requirement for a costimulatory receptor in the generation of T cell memory.

Phenotype and function of human T lymphocyte subsets: consensus and issues.

In recent years, a tremendous effort has been devoted to the detailed characterization of the phenotype and function of distinct T cell subpopulations in humans, as well as to their pathway(s) of differentiation and role in immune responses. But these studies seem to have generated more questions than definitive answers. To clarify issues related to the function and differentiation of T cell subsets, one session of the MASIR 2008 conference was dedicated to this topic. Several points of consensus and discord were highlighted in the work presented during this session. We provide here an account of these points, including the relative heterogeneity of T cell subpopulations during infections with distinct pathogens, the relationship between phenotypic and functional T cell attributes, and the pathway(s) of T cell differentiation. Finally, we discuss the problems which still limit general agreement. Published 2008 Wiley‐Liss, Inc.

Human CD8 + T-cell differentiation in response to viruses

CD8+ T cells are essential in the defence against viruses. Recently, peptide–HLA class I tetramers have been used to study immune responses to viruses in humans. This approach has indicated consecutive stages of human CD8+ T-cell development in acute viral infection and has illustrated the heterogeneity of CD8+ T cells that are specific for latent viruses. Here, we summarize these findings and discuss their significance for our understanding of antigen-induced CD8+ T-cell maturation in humans.

Emergence of a CD4+CD28− Granzyme B+, Cytomegalovirus-Specific T Cell Subset after Recovery of Primary Cytomegalovirus Infection

Cytotoxic CD4+CD28− T cells form a rare subset in human peripheral blood. The presence of CD4+CD28− cells has been associated with chronic viral infections, but how these particular cells are generated is unknown. In this study, we show that in primary CMV infections, CD4+CD28− T cells emerge just after cessation of the viral load, indicating that infection with CMV triggers the formation of CD4+CD28− T cells. In line with this, we found these cells only in CMV-infected persons. CD4+CD28− cells had an Ag-primed phenotype and expressed the cytolytic molecules granzyme B and perforin. Importantly, CD4+CD28− cells were to a large extent CMV-specific because proliferation was only induced by CMV-Ag, but not by recall Ags such as purified protein derivative or tetanus toxoid. CD4+CD28− cells only produced IFN-γ after stimulation with CMV-Ag, whereas CD4+CD28+ cells also produced IFN-γ in response to varicella-zoster virus and purified protein derivative. Thus, CD4+CD28− T cells emerge as a consequence of CMV infection.

Constitutive CD27/CD70 Interaction Induces Expansion of Effector-Type T Cells and Results in IFNγ-Mediated B Cell Depletion

The interaction between the TNF receptor family member CD27 and its ligand CD70 provides a costimulatory signal for T cell expansion. Normally, tightly regulated expression of CD70 ensures the transient availability of this costimulatory signal. Mice expressing constitutive CD70 on B cells had higher peripheral T cell numbers that showed increased differentiation toward effector-type T cells. B cell numbers in CD70 transgenic (TG) mice progressively decreased in primary and secondary lymphoid organs. This B cell depletion was caused by CD27-induced production of IFNgamma in T cells. We conclude that apart from its role in controlling the size of the activated T cell pool, CD27 ligation contributes to immunity by facilitating effector T cell differentiation.

Lethal T cell immunodeficiency induced by chronic costimulation via CD27-CD70 interactions

It has been proposed that HIV-1, in addition to directly infecting and killing CD4+ T cells, causes T cell dysfunction and T cell loss by chronic immune activation. We analyzed the effects of chronic immune activation in mice that constitutively expressed CD70, the ligand for the tumor necrosis factor receptor family member CD27, on B cells. CD70 transgenic (CD70 Tg) mice showed a progressive conversion of naive T cells into effector-memory cells, which culminated in the depletion of naive T cells from lymph nodes and spleen. T cell changes depended on continuous CD27-CD70 interactions and T cell antigen receptor stimulation. Despite this hyperactive immune system, CD70 Tg mice died aged 6–8 months from Pneumocystis carinii infection, a hallmark of T cell immunodeficiency. Thus, persistent delivery of costimulatory signals via CD27-CD70 interactions, as may occur during chronic active viral infections, can exhaust the T cell pool and is sufficient to induce lethal immunodeficiency.

Faces and phases of human CD8+ T-cell development

Abstract After viral infection, naive CD8 + T cells become activated and either differentiate into effector cells, which eliminate virus-infected cells, or convert to memory-type T cells, awaiting re-challenge with virus. Here, Dorte Hamann and colleagues propose a model for antigen-induced differentiation of human CD8 + T cells in vivo and discuss its implications for the lineage relation between memory and effector T cells.

Human NK cells can control CMV infection in the absence of T cells

To the editor: A 3-month-old girl, the first child of consanguineous parents with a family history of unexplained febrile episodes including a death from infection of the eldest brother of the father at 8 months of age, was admitted to our hospital for gastroenteritis. She had a mild leukocytosis (

Timing and tuning of CD27–CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology

Summary:  After binding its natural ligand cluster of differentiation 70 (CD70), CD27, a tumor necrosis factor receptor (TNFR)‐associated factor‐binding member of the TNFR family, regulates cellular activity in subsets of T, B, and natural killer cells as well as hematopoietic progenitor cells. In normal immune responses, CD27 signaling appears to be limited predominantly by the restricted expression of CD70, which is only transiently expressed by cells of the immune system upon activation. Studies performed in CD27‐deficient and CD70‐transgenic mice have defined a non‐redundant role of this receptor–ligand pair in shaping adaptive T‐cell responses. Moreover, adjuvant properties of CD70 have been exploited for the design of anti‐cancer vaccines. However, continuous CD27–CD70 interactions may cause immune dysregulation and immunopathology in conditions of chronic immune activation such as during persistent virus infection and autoimmune disease. We conclude that optimal tuning of CD27–CD70 interaction is crucial for the regulation of the cellular immune response. We provide a detailed comparison of costimulation through CD27 with its closely related family members 4‐1BB (CD137), CD30, herpes virus entry mediator, OX40 (CD134), and glucocorticoid‐induced TNFR family‐related gene, and we argue that these receptors do not have a unique function per se but that rather the timing, context, and intensity of these costimulatory signals determine the functional consequence of their activity.

Development of virus-specific CD4+ T cells during primary cytomegalovirus infection

Although virus-specific CD4(+) T cells have been characterized extensively in latently infected individuals, it is unclear how these protective T-cell responses develop during primary virus infection in humans. Here, we analyzed the kinetics and characteristics of cytomegalovirus-specific (CMV-specific) CD4(+) T cells in the course of primary CMV infection in kidney transplant recipients. Our data reveal that, as the first sign of specific immunity, circulating CMV-specific CD4(+) T cells become detectable with a median of 7 days after first appearance of CMV-DNA in peripheral blood. These cells produce the T helper 1 type (Th1) cytokines IFNgamma and TNFalpha, but not the T helper 2 type (Th2) cytokine IL4. In primary CMV infection, the vast majority of these circulating virus-specific T cells have features of recently activated naive T cells in that they coexpress CD45RA and CD45R0 and appear to be in the cell cycle. In contrast, in people who have recovered from CMV infection earlier in life, virus-specific T cells do not cycle and express surface markers characteristic of memory T cells. After the initial rise, circulating virus-specific CD4(+) T cells decline rapidly. During this phase, a strong rise in IgM and IgG anti-CMV antibody titers occurs, concomitant with the reduction of CMV-DNA in the circulation.