Formation of the Killer Ig-Like Receptor Repertoire on CD4+CD28null T Cells

Although very few CD4+ T cells express killer Ig receptors (KIR), a large proportion of CD4+ T cells with a late memory phenotype, characterized by the absence of CD28, does express KIR. Here, we show that KIR expression on CD4+ T cells is also associated with memory T cell function, by showing that the frequency of CMV-specific cells is higher in CD4+KIR+ than CD4+KIR− T cells. In addition, engagement of an inhibitory KIR inhibited the CMV-specific proliferation of these CD4+KIR+ memory T cells, but had no detectable effect on cytokine production. Our data reveal that, in marked contrast with CD8+ T cells, the activity of a subset of CMV-specific CD4+ T cells is modulated by HLA class I-specific KIR. Thus, the CMV-induced down-regulation of HLA class I may in fact enhance memory CMV-specific CD4+ T cell responses restricted by HLA class II.

Section: Expression Of Functional Inhibitory Kir On Cmv-specific Cd4 supporting

confidence: 75%

Functional Killer Ig-Like Receptors on Human Memory CD4+ T Cells Specific for Cytomegalovirus

Bergen

Kooy-Winkelaar

Dongen

et al. 2009

“…However, the Ag specificities of those populations have not been identified, and autoreactivity is only presumed due to the autologous MLR proliferation. Even though there is no direct evidence implicating these cells in RA, recent studies suggesting the expression of NK markers on CD4 ϩ CD28 Ϫ cells in patients with arthritis lend support to an important role of these cells in pathogenesis (9,34). If these cells were required for autoreactivity leading to the development of arthritis, we would have observed a much more severe disease in CD28-deficient animals.…”

Section: Discussionmentioning

confidence: 81%

Requirement for CD28 May Not Be Absolute for Collagen-Induced Arthritis: Study with HLA-DQ8 Transgenic Mice

Taneja¹,

Taneja

Behrens³

et al. 2005

CD28 is required to achieve optimal T cell activation to an Ag. To determine the role CD28 costimulation plays in collagen-induced arthritis, we have generated DQ8 transgenic, CD28-deficient mice. DQ8 mice deficient for CD28 had comparable numbers of CD4 and CD8 T cells as DQ8.CD28+/+ mice. DQ8.CD28−/− mice develop collagen-induced arthritis with delayed onset and less severity than DQ8.CD28+/+ mice. T cells from DQ8.CD28−/− mice did not respond to type II collagen efficiently in vitro, although the response to DQ8-restricted peptides was similar to that in the parent mice. There was no functional defect in T cells as observed by proliferation with Con A. Cytokine analysis from in vitro study showed the production of high levels of the inflammatory cytokine, IFN-γ, in response to type II collagen. We observed an increase in CD4+CD28−NKG2D+ cells after immunization, suggesting an important role for cells bearing this receptor in the disease process. CD28−/− mice also have an increased number of DX5+ cells compared with CD28+/+ mice, which can lead to the production of high levels of IFN-γ. DQ8.CD28−/− mice had an increased number of cells bearing other costimulatory markers. Cells from DQ8.CD28−/− mice exhibited a lower proliferation rate and were resistant to activation-induced cell death compared with DQ8.CD28+/+ mice. This study supports the idea that CD28 plays a crucial role in the regulation of arthritis. However, in the absence of CD28 signaling, other costimulatory molecules can lead to the development of disease, thus indicating that the requirement for CD28 may not be absolute in the development of arthritis.

“…The promiscuous activity of the KIR3DL1 promoter suggests that the trans-acting factors required for its activity are widely distributed. Given that KIR3DL1 is only expressed in cell populations that also express KIR2DL4 (16,23,30,31), these data implicate mechanisms other than proximal promoter regulation in restricting the expression of the KIR3DL1 gene.…”

Section: Tissue Specificity Of Promoter Activitymentioning

confidence: 82%

“…KIR3DL3 (otherwise known as KIR3DL7 or KIRC1) does not appear to be expressed by the circulating NK cell pool in many donors (29). Most reports indicate that all NK clones and KIR-positive T cell clones express KIR2DL4 transcripts (16,23,24,30,31). The upstream regions of both these KIR genes diverge significantly from those of KIR with variegated expression (26).…”

mentioning

confidence: 99%

Different and Divergent Regulation of the KIR2DL4 and KIR3DL1 Promoters

Stewart

Bergen

Trowsdale

2003

The killer Ig-like receptors (KIR) are a family of highly related MHC class I receptors that show extreme genetic polymorphism both within the human population and between closely related primate species, suggestive of rapid evolutionary diversification. Most KIR are expressed in a variegated fashion by the NK population, giving rise to an NK repertoire of specificities for MHC class I. We compared the promoter for KIR3DL1, which exhibits variegated gene expression, with that for KIR2DL4, which is expressed by all NK cell clones. Maximum transcriptional activity of each was encoded within ∼270 bp upstream of the translation initiation codon. The KIR2DL4 promoter drove reporter gene expression only in NK cells, while the KIR3DL1 promoter was active in a range of cell types, suggesting that the latter requires other regulatory elements for physiological expression. In NK cells, reporter gene expression driven by the KIR2DL4 promoter was greater than that driven by the KIR3DL1 promoter. DNase I footprinting revealed that transcription factor binding sites differ between the two promoters. The data indicate that while the promoters of these two KIR genes share 67% nucleotide identity, they have evolved distinct properties consistent with different roles in regulating the generation of NK repertoire.