Changes in the Composition of Circulating CD8<sup>+</sup>T Cell Subsets during Acute Epstein‐Barr and Human Immunodeficiency Virus Infections in Humans

The immunology of vertical HIV transmission differs from that of adult infection in that the immune system of the infant is not fully matured, and the factors that influence the functionality of CD8+ T cell responses against HIV in children remain largely undefined. We have investigated CD8+ T cell responses in 65 pediatric subjects with vertically acquired HIV-1 infection. Vigorous, broad, and Ag dose-driven CD8+ T cell responses against HIV Ags were frequently observed in children who were older than 3 years of age and maintained CD4+ T cell counts >400 cells/μl. In contrast, younger age or a CD4+ T cell count <400 cells/μl was associated with poor CD8+ T cell responses and high HIV loads. Furthermore, subjects with a severely depleted and phenotypically altered CD4+ T cell compartment had circulating Gag-specific CD8+ T cells with impaired IFN-γ production. When viral load was not suppressed by antiviral treatment, subjects that fell below the putative age and CD4+ T cell count thresholds had significantly reduced CD8+ T cell responses and significantly higher viral loads. Thus, the data suggest that fully effective HIV-specific CD8+ T cell responses take years to develop despite an abundance of Ag in early life, and responses are further severely impaired, independent of age, in children who have a depleted or skewed CD4+ T cell compartment. The results are discussed in relation to differences between the neonatal and adult immune systems in the ability to respond to HIV infection.

Section: Discussionsupporting

confidence: 85%

HIV-Specific CD8+ T Cell Function in Children with Vertically Acquired HIV-1 Infection Is Critically Influenced by Age and the State of the CD4+ T Cell Compartment

Sandberg

Fast

Jordan

et al. 2003

“…In healthy individuals the majority of CD8 ϩ CD27 Ϫ T cells express CD45RA but lack CD28 showing that under physiological conditions CD27 Ϫ and CD28 Ϫ subsets represent largely overlapping populations of CD8 ϩ T cells (7). However, when patients with acute viral infections are being analyzed a very considerable portion of CD45RA Ϫ CD28 Ϫ T cells does express CD27 (25,47). We have postulated that by combined analysis of CD27, CD28, and CD45RA expression, distinct stages of differentiated CD8 T cells can be identified (25).…”

Section: Discussionmentioning

confidence: 99%

Cytolytic Mechanisms and Expression of Activation-Regulating Receptors on Effector-Type CD8+CD45RA+CD27− Human T Cells

Baars

Couto

Leusen

et al. 2000

Circulating CD8+ T cells with a CD45RA+CD27− phenotype resemble cytolytic effector cells because they express various cytolytic mediators and are able to execute cytotoxicity without prior stimulation in vitro. We here demonstrate that CD8+CD45RA+CD27− T cells can use both granule exocytosis and Fas/Fas ligand pathways to induce apoptosis in target cells. The availability of these cytolytic mechanisms in circulating T cells suggests that the activity of these cells must be carefully controlled to prevent unwanted tissue damage. For this reason, we analyzed the expression of surface receptors that either enhance or inhibit T cell function. Compared with memory-type cells, effector cells were found to express normal levels of CD3ε and TCRζ and relatively high levels of CD8. CTLA-4 was absent from freshly isolated effector cells, whereas a limited number of unstimulated memory cells expressed this molecule. In line with recent findings on CD8+CD28− T cells, CD45RA+CD27− T cells were unique in the abundant expression of NK cell-inhibitory receptors, both of Ig superfamily and C-type lectin classes. Binding of NK cell-inhibitory receptors to classical and nonclassical MHC class I molecules may inhibit the activation of the cytolytic machinery induced by either Ag receptor-specific or nonspecific signals in CD8+CD45RA+CD27− T cells.

“…As the sorted CD27 ϩ CD28 Ϫ subset of HCMV-specific CD8 ϩ T cells from M30, which expressed a relatively higher level of perforin, effectively killed target cells, this subset should include effector cytotoxic T cells. A recent study also showed that the CD27 ϩ CD28 Ϫ CD45RO ϩ subset of EBV-specific CD8 ϩ T cells has cytotoxic activity (33). Thus, it is likely that this subset contains memory/effector CD8 ϩ T cells which can kill target cells but may include a wide range of subpopulations between memory and memory/effector phenotypes or various combinations of memory and memory/effector cells in different individuals.…”

Section: The Cd27mentioning

confidence: 99%

Differentiation of Human CD8+ T Cells from a Memory to Memory/Effector Phenotype

Tomiyama

Matsuda

Takiguchi

2002

206

190

Previous studies of perforin expression and cytokine production in subsets of peripheral human CD45RA−CD8+ T cells with different CD28/CD27 phenotypes showed that CD28+CD45RA−CD8+ and CD27+CD45RA−CD8+ T cells have characteristics of memory T cells, whereas CD28−CD45RA−CD8+ and CD27−CD45RA−CD8+ T cells have characteristics of both memory and effector T cells. However, the differentiation pathway from memory CD8+ T cells into memory/effector CD8+ T cells has not been completely clarified. We investigated this differentiation pathway using EBV- and human CMV (HCMV)-specific CD8+ T cells. Three subsets of CD45RA−CD8+ T cells were observed in both total CD8+ T cells and EBV- or HCMV-specific CD8+ T cells: CD27+CD28+, CD27+CD28−, and CD27−CD28−. A significant number of the CD27−CD28+ subset was observed in total CD8 T cells. However, this subset was barely detectable in EBV- or HCMV-specific CD8+ T cells. Analysis of perforin expression and cytotoxic activity in the first three subsets suggested the following differentiation pathway: CD27+CD28+CD45RA−→CD27+CD28−CD45RA−→CD27−CD28−CD45RA−. This was supported by the observation that the frequency of CCR5+ cells and CCR7+ cells decreased during this sequence. Analysis of CCR5 and CCR7 expression in the CD27+CD28+ memory cell subset demonstrated the presence of three CCR5/CCR7 populations: CCR5−CCR7+, CCR5+CCR7+, and CCR5+CCR7−. These findings suggested the following differentiation pathway: CD27+CD28+CD45RA− (CCR5−CCR7+→CCR5+CCR7+→CCR5+CCR7−)→CD27+CD28−CD45RA−→CD27−CD28−CD45RA−. The presence of a CD27−CD28+ subset with a CCR5+CCR7− phenotype implies a specialized role for this subset in the differentiation of CD8+ T cells.