CD11chighCD8+ Regulatory T Cell Feedback Inhibits CD4 T Cell Immune Response via Fas Ligand–Fas Pathway

Abstract

Regulatory T cells can restrict the uncontrolled immune response and inflammation, avoiding pathologic immune injury to the host and thus playing important roles in the maintenance of immune homeostasis. Until recently, many subsets of CD4 and CD8 regulatory T cells have been reported. In this study, we identified CD11chighCD8+ T cells as a new subset of CD8+ regulatory T cells. During Listeria monocytogenes and Staphylococcus aureus infection, two subsets of CD8 T cells were classified according to the expression level of CD11c, including CD11clowCD8+ and CD11chighCD8+ T cells. CD11clowCD8+ T cells, existing during the whole period of infection, act as conventional activated T cells to kill target cells in a perforin-dependent manner. Interestingly, CD11chighCD8+ T cells appeared only at a late stage of infection, expressed relatively high CD122 and low CD69, did not secrete IFN-γ, IL-10, TGF-β, and exhibited much more potent cytotoxicity against target cells via Fas ligand–Fas pathway in an Ag-independent manner. Ligation of CD11c was important in the cytotoxicity of CD11chighCD8+ T cells. Furthermore, CD11chighCD8+ T cells could directly kill the activated CD4 T cells both in vitro and in vivo, whereas CD11clowCD8+ T cells could not. Thus, we identified an infection-induced new subset of CD11chighCD8+ regulatory T cells, which might contribute to protect host from pathological immune injure. Our results indicate that CD11c+CD8+ T cells are constitute a heterogeneous population that can be divided further into regulatory CD11chighCD8+ T cell subset and effector CD11clowCD8+ T cell subset, thus adding insight to the role of CD8 T cells in immune response and regulation.

CD8+CD122+CD49dlowregulatory T cells maintain T-cell homeostasis by killing activated T cells via Fas/FasL-mediated cytotoxicity

“…However, our experimental results obtained in the former studies (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and the present studies have definitely shown the regulatory activity in this T-cell subset. Our current interpretation is that the regulatory and the memory functions are compatible.…”

“…+ T cells in fact regulates the immune response (28). This is the first report describing that CD8 + Treg cells directly control CD8 …”

Advances on Non-CD4 + Foxp3+ T Regulatory Cells

“…However, in the 40 years since their original description, CD8+ Tregs have been categorized into several distinct phenotypes including: a) Qa-1/HLA-restricted Tregs (5-7); b) CD8+CD122+ Tregs (8); c) CD8+CD28- Tregs (9); d) CD8+Foxp3+ Tregs (10); e) CD8+CD103+ Tregs (11); f) CD8+LAG-3+Foxp3+CTLA-4+ Tregs (12); g) CD8+IL-10+CCR7+CD45RO+ Tregs (13); h) CD8+CD45RC low Tregs (14); i) CD8+CD122+PD-1+ Tregs (15) and j) CD8+CD11c high Tregs (16) (Table 1). CD8+ Tregs can arise within the thymus as naturally occurring CD8+ Tregs or they can be induced in peripheral tissues by a variety of maneuvers including donor-specific transfusion (17), injection of antigen into the anterior chamber (AC) of the eye (18), anti-idiotype immunization with allospecific T cells or MHC-derived peptides (19, 20), or by in vivo immunization combined with blockade of CD40 co-stimulatory molecules (21).…”

“…Contact-dependent suppression by CD8+ Tregs involves the direct killing of CD4+ T effector cells by perforin-mediated cytolysis (25, 26) or FasL-induced apoptosis (16). In addition to suppressing effector T cells, CD8+Foxp3+ Tregs are capable of inducing the de novo generation of CD4+Foxp3+ Tregs by a process that is contact-dependent and requires the production of soluble TGF-β (27), and is reminiscent of a phenomenon that has been previously described as “infectious tolerance”.…”

Applying Convergent Immunity to Innovative Vaccines Targeting Staphylococcus aureus

“…While such tolerance may prevent a potentially harmful inflammatory response to commensal S. aureus , it may also impair effective immune responses to invasion or re-infection. Similarly, a regulatory subset of CD8 + /CD11c hi T cells has been shown to emerge in the setting of S. aureus infection (106). This regulatory subset may inhibit appropriate CD4+ T-cell polarization in response to the organism.…”