Control of T Cell Reactivation by Regulatory Qa-1–Restricted CD8+ T Cells

Abstract

Administration of attenuated pathogenic T cell clones, a procedure known as T cell vaccination, induces CD8+ T cells specific for peptides derived from the Vβ-chain of the TCR presented by the MHC class Ib molecule, Qa-1 expressed on the vaccine cells. These regulatory CD8+ T cells have the capacity to control the activation of endogenous T cells expressing the same TCR Vβ-chain as the vaccinating cells. We hypothesized that vaccination with NKT cells could also induce Qa-1–restricted CD8+ T cells that would control NKT cell activation. We tested this hypothesis in a murine model of Con A-induced hepatitis that is induced by NKT cells. Vaccination with NKT cells effectively induced protective Qa-1–restricted CD8+ T cells that prevented hepatitis. Surprisingly, upon vaccination with T cells expressing Vβ-chains irrelevant to NKT cells, we discovered that the specificity of vaccine-induced Qa-1–restricted CD8+ T cells was not limited to the Vβ-chain of the vaccinating cells. We further show that these regulatory Qa-1–restricted CD8+ T cells arise spontaneously upon polyclonal activation of T cells in the absence of deliberate T cell vaccination. These experiments provide new insight into a CD8+ T cell compartment that regulates the immediate reactivation of conventional T cells and NKT cells.

Small Intestinal Intraepithelial Lymphocytes Expressing CD8 and T Cell Receptor γδ Are Involved in Bacterial Clearance during Salmonella enterica Serovar Typhimurium Infection

“…As Qa-1 is the ligand of inhibitory receptor NKG2A, its downregulated expression on IECs may attenuate the inhibitory signal recognized by CD8 ϩ TCR␥␦ ϩ iIELs, leading to a reduction in the activation threshold of iIELs. In accordance with this, the human counterpart of Qa-1, HLA-E, was found to participate in a negative-feedback loop on cytotoxic T lymphocyte (CTL) responses in which TCR stimulation upregulates NKG2A expression and, in turn, NKG2A downregulates TCR activation by modifying antigen activation thresholds (12,13,27). The decreased expression of Ly49E and Ly49F on CD8 ϩ TCR␥␦ ϩ iIELs may also contribute to this effect.…”

Control of the T Follicular Helper–Germinal Center B-Cell Axis by CD8 + Regulatory T Cells Limits Atherosclerosis and Tertiary Lymphoid Organ Development

“…[12][13][14][15][16] Previously unsuspected cell targets of CD8 + Tregs are Tfh cells because of their high basal expression of the Qa-1 molecule, 14 which is the mouse ortholog of the HLA-E molecule. The Qa-1 molecule can establish 2 types of molecular interactions: One with T cell receptors (TCRs) on CD8 + Tregs and the other with NKG2A receptors on CD8 + T cells and natural killer cells.…”

A naturally occurring CD8+CD122+ T-cell subset as a memory-like Treg family

“…The same cells also reportedly induced CD4 1 T-cell anergy 5 and regulated reactivation of T and NKT cells. 6 Furthermore, antigen-induced CD8 1 CD103 1 Tregs have been shown to suppress effector T-cell function 7 and to be significantly increased in spontaneously tolerant recipients of liver allografts. 8 It has also been reported that Qa-1-restricted CD8 1 T cells regulate the activation of T cells as well as NKT cells.…”

“…8 It has also been reported that Qa-1-restricted CD8 1 T cells regulate the activation of T cells as well as NKT cells. 6 Therefore, CD8 1 CD28 2 , CD8 1 Qa-1 1 or CD8 1 CD103 1 Treg subsets may share the responsibility of maintaining immune homeostasis with other regulatory cell families, including CD4 1 CD25 1 FoxP3 1 and CD8 1 CD122 1 Tregs, although it remains to be defined whether and how the latter cells are associated with CD8 1 CD28 2 , CD8 1 CD103 1 or other CD8 1 Treg subsets. Understanding the relationship between CD8 1 CD122 1 and other subsets of CD8 1 Tregs through future studies may help in the design of new strategies to optimize their suppressive efficacy.…”