Phenotypic and Functional Characterization of CD4 T Cells Expressing Killer Ig-Like Receptors

Abstract

Killer Ig-like receptors (KIR) are commonly found on human NK cells, γδ T cells, and CD8 T cells. Although KIR+ CD4 T cells are found in certain patients, their prevalence in healthy donors is controversial. We now provide definitive proof that such cells are present in most individuals, and report on their frequency, surface phenotype, cytokine profile, and Ag specificity. The number of KIR+ CD4 T cells detected in peripheral blood increased with age. In contrast with regular KIR− CD4 T cells, the majority of KIR+ CD4 T cells lacked surface expression of CD27, CD28, CCR4, and CCR7, but did express CD57 and 2B4. In addition, KIR were detected on approximately one-tenth of CD28− and CD57+ memory CD4 T cells. In line with the absence of the Th2 marker CCR4, the KIR+ CD4 cells produced mainly IFN-γ and little IL-4, IL-10, or IL-17 upon TCR triggering. Furthermore, the KIR+ population contained cells that responded to recall Ags in an HLA class II-restricted fashion. Together, our data indicate that KIR-expressing CD4 T cells are predominantly HLA class II-restricted effector memory Th1 cells, and that a significant, previously unrecognized fraction of effector memory Th1 cells expresses KIR.

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…KIR expression is weak or absent in immature NKG2A + CD56 bright NK cells and increases gradually with maturation, reaching its maximum level in NKG2A −  CD56 dim NK cells 148, 149, 150. Similar observation was made for T cells, in which KIR expression is virtually absent in CD4 and CD8 naive T cells and reaches its maximal level in differentiated effector memory T cells 2, 5, 151, 152. Accordingly, KIR expression is low in less mature cord blood NK and T cells compared with healthy adult control cells 153, 154…”

Activating NK‐cell receptors co‐stimulate CD4+CD28− T cells in patients with rheumatoid arthritis

“…Recent literature has demonstrated the expression of NKR on CD4 1 CD28 À T cells but their definitive role remains elusive [9,[13][14][15]. Activating receptors may fine-tune the thresholds for TCR signaling and potentiate the effector response of the T cells [15].…”

“…Under such circumstances several of the described NKR were shown to have a direct co-stimulatory role on CD4 1 CD28 À T cells, leading to increased effector function upon TCR stimulation [5,14,21]. However, it is unclear whether triggering of NKR alone or in a pair-wise fashion on primary ''resting'' CD4 1 CD28 À T cells yields enhanced effector functions.…”

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

“…During the final stages of this process, characterized mainly by the loss of the costimulatory receptor CD28, T cells acquire a surface phenotype commonly associated with NK cells, such as the acquisition of killer Ig-like receptors (KIR) 3 (6,7). However, it is less clear whether KIR are frequently found on T cells responding to previously encountered Ags.…”

“…The inhibitory receptors bind classical HLA class I molecules, while the physiological ligands for the activating KIR are mostly unknown. By FACS, KIR expression is detected on the large majority of NK cells, ϳ5% of CD8 ϩ T cells (6), and 0.2% of CD4 ϩ T cells (7). The role of KIR in regulating NK cell responses is reasonably well understood, but their role in T cell responses has remained largely enigmatic (11).…”