Regulation of Activated CD4+ T Cells by NK Cells via the Qa-1–NKG2A Inhibitory Pathway

Abstract

The ability of natural-killer cells to regulate adaptive immunity is not well understood. Here we define an interaction between the class Ib major histocompatibility complex (MHC) molecule Qa-1-Qdm on activated T cells responsible for adaptive immunity and CD94-NKG2A inhibitory receptors expressed by natural-killer cells by using Qa-1-deficient and Qa-1 knockin mice containing a point mutation that selectively abolishes Qa-1-Qdm binding to CD94-NKG2A receptors. The Qa-1-NKG2A interaction protected activated CD4+ T cells from lysis by a subset of NKG2A+ NK cells and was essential for T cell expansion and development of immunologic memory. Antibody-dependent blockade of this Qa-1-NKG2A interaction resulted in potent NK-dependent elimination of activated autoreactive T cells and amelioration of experimental autoimmune encephalomyelitis. These findings extend the functional reach of the NK system to include regulation of adaptive T cell responses and suggest a new clinical strategy for elimination of antigen-activated T cells in the context of autoimmune disease and transplantation.

Generation and Regulation of CD8+ Regulatory T Cells

“…In addition, Qa-1 complexed to the Qdm peptide engages the CD94/NKG2 receptor expressed by CD8 cells and NK cells and attenuates the activities of these cells (22)(23)(24). As a result, the immune response phenotype of Qa-1-deficient mice reflects two opposing effects.…”

“…As a result, the immune response phenotype of Qa-1-deficient mice reflects two opposing effects. Enhanced CD4-dependent immunity reflects loss of the Qa-1 target for CD8 + Treg activity (21), while reduced CD4-dependent immunity results from lysis of activated CD4 + cells by NK cells that are unencumbered by an inhibitory NKG2A-Qa-1/Qdm interaction (24).…”

“…A second Qa-1 amino acid mutant (Qa-1 R72A) knock-in mouse strain was also developed that disrupts Qa-1 binding to NKG2A expressed by NK cells and CD8 + cells, rendering CD4 + cells vulnerable to NK and CD8 + cells lysis, but sparing Qa-1-dependent peptide presentation to the TCR (24). Interestingly, genetic interruption of this interaction in Qa-1 R72A knock-in mice allows development of robust CD8 + Treg activity and complete resistance to the development of EAE.…”

NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells

“…It has been reported that NK cells regulate T cell responses through multiple direct and indirect mechanisms, including NK cell-mediated killing of activated CD8 + T cells (14,15,(18)(19)(20)(21), CD4 + T cells (18,19,22,23), and also of dendritic cells (DCs) (12,24,25). However, little is known about a possible NK cell-mediated inhibitory/regulatory role during antitumor immune responses.…”

Therapeutic implications of NK cell regulation of allogeneic CD8 T cell-mediated immune responses stimulated through the direct pathway of antigen presentation in transplantation

“…This interaction confers CD4 T cells with resistance to NK cell-mediated lysis. 43 Another example of this shielding applies also to CD8 T cells expressing CD48 that inhibit NK cells through interaction with 2B4 (CD244). 44,45 We found no evidence that NK cells were regulating the size of the CD8 T cell pool, as shown in Figure 4A, by killing activated alloreactive CD8 T cells because CD8 T cell counts were not affected in the absence of NK cells.…”