CD4 Expression on Activated NK Cells: Ligation of CD4 Induces Cytokine Expression and Cell Migration

Abstract

NK cells play an important role in the innate immune response. We have isolated NK cells from human lymphoid tissues and found that these cells express the CD4 molecule on their surface at levels higher than those found on peripheral blood NK cells. To study the functional role of the CD4 molecule on NK cells, we developed an in vitro system by which we are able to obtain robust CD4 expression on NK cells derived from blood. CD4+ NK cells efficiently mediate NK cell cytotoxicity, and CD4 expression does not appear to alter lytic function. CD4+ NK cells are more likely to produce the cytokines γ-IFN and TNF-α than are CD4− NK cells. Ligation of CD4 further increases the number of NK cells producing these cytokines. NK cells expressing CD4 are also capable of migrating toward the CD4-specific chemotactic factor IL-16, providing another function for the CD4 molecule on NK cells. Thus, the CD4 molecule is present and functional on NK cells and plays a role in innate immune responses as a chemotactic receptor and by increasing cytokine production, in addition to its well-described function on T cells as a coreceptor for Ag responsive cell activation.

Functionally distinct subsets of human NK cells and monocyte/DC-like cells identified by coexpression of CD56, CD7, and CD4

“…17 In agreement with a previously published report, 25 we observed a distinct population of peripheral blood CD56 ϩ CD3/14/ 19 neg cells expressing CD4 ( Figure 1A) that comprised 0.2% to 7.5% of the peripheral blood CD56 ϩ cell population ( Figure 1B) within the lymphocyte gate. To distinguish between CD4 ϩ CD56 ϩ NK cells and other potentially contaminating cell types, such as monocytic or dendritic cells, we used CD7 as an additional NK cell-specific marker.…”

“…The only significant difference observed in this study pertained to the activation status of the CD7 ϩ CD4 ϩ NK cells. In agreement with a previous report proposing that CD4 ϩ NK cells are activated and capable of producing cytokines, 25 we observed that a significantly greater percentage of CD7 ϩ CD4 ϩ NK cells express the T helper 1 chemokine receptor CXC chemokine receptor 3 (CXCR3) and possess significantly higher levels of glucocorticoid-induced tumor necrosis factor (TNF) receptor (GITR; Figure 3L-M). We also observed that approximately 30% and 18% of the IFN␥ ϩ NK cells express CD4 after IL-12 plus IL-18 and K562 stimulation, respectively (data not shown).…”

“…Unlike NKp46, which is not readily detected on all human NK cells 11,42 and can be downregulated under some physiologic conditions, [42][43][44] CD7 is expressed homogeneously by all NK cells and does not appear to be significantly down-regulated after activation. Although our results confirm that CD4 ϩ CD56 ϩ NK cells are indeed activated NK cells, 25,26 the use of CD7 in our study provides for a precise determination of the percentage of activated NK cells present in the blood of healthy donors and allows for analysis of their functional behavior. Because the majority of CD4 ϩ CD56 ϩ cells are CD7 neg monocyte/DC-like cells, we now demonstrate that the frequency of activated NK cells in blood is much lower (1.44% Ϯ 0.99% of CD56 ϩ cells) than previously reported.…”

“…In contrast to freshly isolated, resting human NK cells, activated human NK cells can express human leukocyte antigen DR (HLA-DR), OX40 ligand, CD80, and CD86 and have been shown previously to have antigen-presenting capabilities similar to certain DC subsets. [22][23][24] Activated NK cells can also express CD4 on their surface, 25,26 a molecule typically found on a subset of CD3 ϩ T cells and monocytes/macrophages; however, CD4 has also been observed on many activated cell types including CD8 ϩ T cells, 27 B cells, 28 monocytes, 29 eosinophils, 30 and neutrophils. 31 Given the small percentage of circulating CD4 ϩ NK cells, previous studies have used in vitro stimulation protocols to expand the number of NK cells expressing CD4 25,26 ; however, these activated CD4 ϩ NK cells may not be representative of CD4 ϩ NK cells in vivo.…”

T Cell Infiltrates in the Muscles of Patients with Dermatomyositis and Polymyositis Are Dominated by CD28null T Cells

“…Coexpression of CD244 and CD3 was used to identify CD28 null T cells. To exclude CD4 dim macrophages/monocytes and NK cells which also might express CD244 (25), the combination of CD3 and CD4 in the three-color stainings was used to identify CD4 ϩ T cells. To identify CD8 ϩ T cells in the very same section, a lack of CD4 in presence of CD3 was used.…”