Uncoupling of T-cell effector functions by inhibitory killer immunoglobulin–like receptors

Abstract

IntroductionImmune homeostasis is tightly regulated by negative regulatory signals providing a counterbalance to activating stimuli. 1,2 Negative regulatory receptors have been described on all hematopoietic cells; a prime example that illustrates their importance is natural killer (NK) cell function. Self tolerance of NK cells is ensured by a set of inhibitory cell surface receptors that bind to self-major histocompatibility (MHC) class I ligands. 3 In humans, these receptors include the family of killer immunoglobulin-like receptors (KIRs).Inhibitory KIRs have long cytoplasmic tails with 2 immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Upon ligation of an inhibitory KIR, the ITIMs are phosphorylated and bind to the src homology 2 (SH2) domains of the phosphatase SHP-1. As a result of this binding, the catalytic site of SHP-1 is released from autoinhibition. 4 In NK cells, cognate binding of inhibitory KIRs to their human leukocyte antigen (HLA) ligands is enough to facilitate receptor clustering, ITIM phosphorylation, and SHP-1 activation. 5 The direct target of SHP-1 appears to be the guanine nucleotide exchange factor Vav1. 6 Dephosphorylation of Vav1 leads to inhibition of Rac1, 6 thereby preventing cytoskeletal rearrangement. One consequence is complete inhibition of NK cell activation. In fact, the formation of an activation platform between NK cells and target cells is completely prevented. 7 In addition to NK cells, KIRs are also expressed on T cells. 8,9 Naive and memory T cells are equipped to support their transcription; 10 however, expression is only found on senescent or enddifferentiated CD4 ϩ and CD8 ϩ T cells that have lost the expression of CD28. 11 The biologic function of inhibitory KIR expression on T cells is difficult to envision and likely different from NK cells. In NK cells, they are the basis for the missing self hypothesis 12 (ie, NK cells only respond to cells that have lost MHC class I expression). Otherwise, the inhibitory receptors keep NK cells completely unresponsive. Such a model would not be meaningful for T cells, the activation of which is dependent on MHC-restricted T-cell-receptor (TCR) triggering. Not surprisingly, functional studies of inhibitory receptors on T cells have come to conflicting results. 8,13,14 Inhibitory KIRs on selected tumor-specific CD8 ϩ T cells in patients with melanoma 15 and renal carcinoma were shown to inhibit tyrosine phosphorylation of early signaling proteins, lipid rafts, TCR/CD3 clustering, and the reorganization of the actin cytoskeleton; they also completely shut down T-cell activation. Consequently, the tumor-specific immune response was dampened, supporting a model of KIR expression on T cells as a cause of defective immunosurveillance. 8 Other studies of inhibitory receptors, such as immunoglobulin-like transcript 2 (ILT-2) on human CD8 T cells and GP49B1 on murine CD8 T cells, have only G.H. designed research, performed research, analyzed data, and wrote the paper; K.S. performed research and analyzed data; D.C. performed rese...

BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties

“…This phenomenon may be due to the unique signaling of KIRs on human CD8 C T cells; previous studies have found that their presence on CD8 C CD28 ¡ T cells, unlike NK cells, only inhibits complex cellular functions such as proliferation, while leaving certain effector functions such as cytotoxicity essentially intact, presumably because of delayed recruitment to the TCR synapse after activation. 39 Additionally, although there was discordance between enrichment of multiple KIR gene transcripts in the CD8 C BTLA ¡ TIL and a few KIRs being expressed at the protein level in our present study, this might be explained by recent findings in which human CD8 C T cells, unlike NK cells, were found to generally express only one activating or inhibitory KIR. 40 Our gene expression studies also give some insights into the issue of inhibitory receptors and CD8 C T-cell exhaustion.…”

Differential Pathways Govern CD4+CD28− T Cell Proinflammatory and Effector Responses in Patients with Coronary Artery Disease

“…In the same context and in line with our observations, a recent study has shown that KIRs on T cells function fundamentally differently from the regulatory KIRs on NK cells (43). Investigations of KIR2DL2 regulation of CD4 ϩ CD28 Ϫ cell function showed that its engagement by HLA-cw3 had no effect on conjugate formation between T cells and target cells, leading to formation of activating immune synapses and induction of cytotoxicity.…”

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

“…Therefore, signaling via inhibitory and activating KIR may intersect some but not other signaling pathways linked to the TCR. In support of this idea, binding of HLA-C by the inhibitory KIR2DL2 affects late but not early TCR-induced intracellular signals and did not inhibit cytotoxicity of CD4 ϩ CD28 Ϫ T cell clones from RA patients in multiple clones and over a wide range of stimulatory signals (44). The down-regulation of HLA class I by CMV is therefore likely to have quantitative and qualitative effects on the response of CD4 ϩ KIR ϩ T cells.…”