Identification of a human CD8⁺regulatory T cell subset that mediates suppression through the chemokine CC chemokine ligand 4

Abstract

Regulatory T cells (Treg) comprise multiple subsets and are important in controlling immunity and inflammation. However, the induction and mode of action of the various distinct Treg subsets remain ill defined, particularly in humans. Here, we describe a human CD8 ؉ lymphocyte activation gene-3 (LAG-3) ؉ CD25 ؉ FoxP3 ؉ Treg subset, which suppresses T cells partly through the secretion of CC chemokine ligand 4 (CCL4), which can inhibit T cell activation by interfering with T cell receptor signaling. CD8 ؉ Tregs are expanded by antigen in in vivo-primed donors, and can be detected in pathogeninfected human tissue. This CD8 ؉ LAG-3 ؉ CD25 ؉ FoxP3 ؉ CCL4 ؉ Treg subset thus may play a role in immunoregulation in humans, including infectious diseases.infectious diseases

LAG-3 Expression Defines a Subset of CD4+CD25highFoxp3+ Regulatory T Cells That Are Expanded at Tumor Sites

“…LAG-3 has been shown to play a key role in T cell homeostasis and has been associated with murine CD4 + and CD8 + Treg cells (25,40). Moreover, recent data in humans identified a new subset of CD8 + Treg cells expressing LAG-3 that mediate immunosuppression via the secretion of CCL4 (29). Based on these observations, we analyzed the expression of this marker in human CD4 + T cells to explore its distribution in relation to CD25 and its involvement in human Treg cells.…”

“…There is increasing evidence on the role of LAG-3 in the downregulation of T cell responses (27) and on its involvement in tumor-infiltrated Treg function in Hodgkin's lymphoma (28). Similarly, an Ag-specific LAG-3 + CD25 + Foxp3 + induced regulatory CD8 + T cell subset has been identified in a series of patients with tuberculosis (29).…”

The Upregulation of LAG-3 on T Cells Defines a Subpopulation with Functional Exhaustion and Correlates with Disease Progression in HIV-Infected Subjects

“…LAG-3 also defines an active CD4 + CD25 high Foxp3 + regulatory T cell subset, the fre-quency of which is enhanced in the PBMCs of cancer patients (26). There is increasing evidence of the role of LAG-3 and its involvement in regulatory T cell functions (27,28).…”

In vitroinduced CD8+regulatory T cells inhibit skin inflammation

“…Here, the most prominent population is CD8 + CD28 -and suppressive via IL-10 secretion [8]. Furthermore, the induction of CD8 + regulatory T cells through the stimulation of the T-cell receptor mostly leads to the expression of Foxp3 in these T cells [3,4,[9][10][11]. Most of the adaptive CD8 + regulatory T cells appear to suppress via a cell-contact-dependent mechanism.…”

“…They express CD25, CTLA-4, GITR and Foxp3 (forkhead box protein 3) and suppress in a contact-dependent manner via CTLA-4 and TGF-β [1]. Interestingly, various phenotypes of induced CD8 + regulatory T cells seem to exist in humans and in experimental animals [2][3][4][5][6][7]. Here, the most prominent population is CD8 + CD28 -and suppressive via IL-10 secretion [8].…”