Laila E. Gamadia

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.

Proliferation Requirements of Cytomegalovirus-Specific, Effector-Type Human CD8+ T Cells

Two prototypic types of virus-specific CD8+ T cells can be found in latently infected individuals: CD45R0+CD27+CCR7− effector-memory, and CD45RA+CD27−CCR7− effector-type cells. It has recently been implied that CD45RA+CD27−CCR7− T cells are terminally differentiated effector cells and as such have lost all proliferative capacity. We show in this study, however, that stimulation of CMV-specific CD45RA+CD27−CCR7− T cells with their cognate peptide in concert with either CD4+ help or IL-2, IL-15, or IL-21 in fact induces massive clonal expansion. Concurrently, these stimulated effector T cells change cell surface phenotype from CD45RA to CD45R0 and regain CCR7, while effector functions are maintained. Our data imply that CD45RA+CD27−CCR7− effector-type T cells contribute to immunity not only by direct execution of effector functions, but also by yielding progeny in situations of viral reinfection or reactivation.

The Size and Phenotype of Virus-Specific T Cell Populations Is Determined by Repetitive Antigenic Stimulation and Environmental Cytokines

Based on the expression of the TNFR SFP CD27, two Ag-primed CD8+ T cell subsets can be discerned in the circulation of healthy individuals: CD27+ T cells that produce a variety of cytokines but do not display immediate cytolytic activity; and cytotoxic CD27− T cells, which secrete only IFN-γ and TNF-α. The mechanism that controls the generation of these different phenotypes is unknown. We show that CMV reactivation not only increases the number of virus-specific T cells but also induces their transition from a CD27+ to a CD27− phenotype. In support of a relation between pool size and phenotype in a cohort of latently infected individuals, the number of Ag-specific CD27− CD8+ T cells was found to be linearly related to the total number of CMV-specific CD8+ T cells. In vitro studies revealed that the acquisition of the CD27− phenotype on CMV-specific T cells depended on the interaction of CD27 with its cellular ligand, CD70. Expression of CD70 was proportional to the amount of antigenic stimulation and blocked by the CD4+ T cell-derived cytokine IL-21. Thus, induction of CD70, which may vary in distinct viral infections, appears to be a key factor in determining the size and phenotype of the CMV-specific T cell population in latently infected individuals.

Cross-reactivity of cytomegalovirus-specific CD8(+) T cells to allo-major histocompatibility complex class I molecules

Background. In transplantation settings, cytomegalovirus (CMV) infection is a common complication. CMV infection is associated with a higher incidence of graft rejection in solid organ transplantation and graft-versus-host disease in bone marrow transplantation. The underlying mechanism of this association could be the generation of CMV-specific CD8+ T cells capable of cross-reacting with alloantigens present on graft and host, respectively. Methods. Whereas as to date, no direct ex vivo analysis can be performed of the CD8+ T-cell repertoire directed at allo-major histocompatibility complex (MHC) class I molecules, virus-specific cells can be readily enumerated by use of MHC-peptide tetrameric complexes. In this study, the authors used this technique to analyze potential overlapping CD8+ T-cell repertoires between self-MHC–viral peptide and allo-MHC complexes by stimulating CMV-specific CD8+ T cells with alloantigens. Results. The authors found that CMV-specific CD8+ T cells are activated and proliferate on stimulation with alloantigens. Conclusions. Although these cells are cytotoxic against CMV-peptide pulsed target cells, no cytotoxicity of CMV-specific cells to alloantigens could be detected, inferring that there are other mechanisms of graft damage by alloantigen-stimulated virus-specific CTL.

T-lymphocyte subset distribution in human spleen

Background  When analyzing human cellular immune responses, most focus is placed on the peripheral blood (PB) and, to a lesser extent, the lymph nodes. To date the spleen has not been analyzed with regard to its role in adaptive cellular immunity and more notably not with respect to T‐cell immune responses.

Skewed maturation of virus-specific CTLs?

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