Physiological Induction of Regulatory Qa-1-Restricted CD8+ T Cells Triggered by Endogenous CD4+ T Cell Responses

Abstract

T cell-dependent autoimmune diseases are characterized by the expansion of T cell clones that recognize immunodominant epitopes on the target antigen. As a consequence, for a given autoimmune disorder, pathogenic T cell clones express T cell receptors with a limited number of variable regions that define antigenic specificity. Qa-1, a MHC class I-like molecule, presents peptides from the variable region of TCRs to Qa-1-restricted CD8+ T cells. The induction of Vß-specific CD8+ T cells has been harnessed in an immunotherapeutic strategy known as the “T cell vaccination” (TCV) that comprises the injection of activated and attenuated CD4+ T cell clones so as to induce protective CD8+ T cells. We hypothesized that Qa-1-restricted CD8+ regulatory T cells could also constitute a physiologic regulatory arm of lymphocyte responses upon expansion of endogenous CD4+ T cells, in the absence of deliberate exogenous T cell vaccination. We immunized mice with two types of antigenic challenges in order to sequentially expand antigen-specific endogenous CD4+ T cells with distinct antigenic specificities but characterized by a common Vß chain in their TCR. The first immunization was performed with a non-self antigen while the second challenge was performed with a myelin-derived peptide known to drive experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. We show that regulatory Vß-specific Qa-1-restricted CD8+ T cells induced during the first endogenous CD4+ T cell responses are able to control the expansion of subsequently mobilized pathogenic autoreactive CD4+ T cells. In conclusion, apart from the immunotherapeutic TCV, Qa-1-restricted specialized CD8+ regulatory T cells can also be induced during endogenous CD4+ T cell responses. At variance with other regulatory T cell subsets, the action of these Qa-1-restricted T cells seems to be restricted to the immediate re-activation of CD4+ T cells.

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.…”

Bridging the gap from genetic association to functional understanding: the next generation of mouse models of multiple sclerosis

“…As we have previously described, epitope spreading was also observed in our humanized transgenic mouse model in which disease was initiated by transgenic CD8 + T cells restricted by a TCR that recognizes PLP [45][46][47][48][49][50][51][52][53] in the context of HLA-A*0301. The initial CNS damage caused by this first assault was attributed to the release of myelin antigens from injured cells, such that MOG 35-55 -specific CD4 + T cells conferred disease in its latter stages; however, this has not been confirmed (45).…”

“…More recently, a population of regulatory CD8 + T cells has been defined and are restricted by the MHC class Ib molecule, Qa‐1 (HLA‐E in humans), which can present both self and exogenous peptides to TCRs on CD8 + T cells and drive their regulatory phenotype. These regulatory CD8 + T cells have been shown to be able to suppress both antibody‐ (48) and CD4 + T cell‐mediated responses in EAE (49), where Qa‐1 deficient mice display increased disease severity following immunization (50).…”

Increased mitochondrial apoptotic priming of human regulatory T cells after allogeneic hematopoietic stem cell transplantation

“…9,12,[30][31][32][33][34][35][36][37][38][39][40] CD4 Treg have clearly defined phenotypic and functional characteristics and, as a result, have been studied extensively in various models of GvHD as well as in clinical studies. The relative deficiency of CD4 Treg after allogeneic HSCT appears to contribute to both acute and cGvHD, and this observation has prompted efforts to understand the mechanisms responsible for the inadequate reconstitution of this important T-cell subset after transplant.…”