IL‐12 and IL‐4 activate a CD39‐dependent intrinsic peripheral tolerance mechanism in CD8⁺ T cells

Abstract

Immune responses to protein antigens involve CD4+ and CD8+ T cells, which follow distinct programs of differentiation. Naïve CD8 T cells rapidly develop cytotoxic T‐cell (CTL) activity after T‐cell receptor stimulation, and we have previously shown that this is accompanied by suppressive activity in the presence of specific cytokines, i.e. IL‐12 and IL‐4. Cytokine‐induced CD8+ regulatory T (Treg) cells are one of several Treg‐cell phenotypes and are Foxp3− IL‐10+ with contact‐dependent suppressive capacity. Here, we show they also express high level CD39, an ecto‐nucleotidase that degrades extracellular ATP, and this contributes to their suppressive activity. CD39 expression was found to be upregulated on CD8+ T cells during peripheral tolerance induction in vivo, accompanied by release of IL‐12 and IL‐10. CD39 was also upregulated during respiratory tolerance induction to inhaled allergen and on tumor‐infiltrating CD8+ T cells. Production of IL‐10 and expression of CD39 by CD8+ T cells was independently regulated, being respectively blocked by extracellular ATP and enhanced by an A2A adenosine receptor agonist. Our results suggest that any CTL can develop suppressive activity when exposed to specific cytokines in the absence of alarmins. Thus negative feedback controls CTL expansion under regulation from both nucleotide and cytokine environment within tissues.

Human CD8+ T Cells in Asthma: Possible Pathways and Roles for NK-Like Subtypes

“…It should be borne in mind that, in the various existing studies, CD8+ T cells were retrieved and characterized using different methodological approaches in terms of patient groups or murine models, biological samples, and study methods. These aspects may account for most of the discrepancies observed, which have indeed been clustering around a non-relevant role (4), a protective role (5), or a disease-favoring role, including association with poorer lung function (6–10) and possibly involving a significant direct and indirect contribution toward a Th2-high bronchial inflammation (11, 12). Nevertheless, it should also considered that different conditions of the local milieu in the target organ, possibly involving exposure to different cytokines and/or antigen-producing cells may also explain discrepant results across existing studies.…”

“…Another study, involving asthmatic patients who were followed up for 14 years showed that the decline in lung function (FEV 1 ), although mild, was clearly correlated with the number of CD8+ T-cells in airway biopsies, not just at baseline but also on follow-up (5). Curiously, a recent study in asthmatic patients demonstrated that the degree of airflow obstruction (FEV 1 and FEF 25–75 ) was correlated not with the total number of CD8+ T cells but rather with the number of CD8+ T-cells in the bronchoalveolar lavage fluid which expressed the high-affinity receptor for leukotriene B4 (BLT1) and produced IL-13 (10).…”

“…In fact, in the presence of IL-4 and IL-12, murine CD8+ T cells have been shown to become CD39+ Foxp3-negative “regulatory” T cells that demonstrate suppressive activity via production of IL-10 and contact-dependent mechanisms (5). Furthermore, memory CD8+ T cells present in the airways of mice after an influenza infection have been shown to suppress the development of subsequent Th2-driven allergic inflammation in an IFN-gamma dependent way (37).…”

Which CD8+ T-cells in asthma? Attacking or defending?

“…Asthma has been traditionally associated with an expansion of CD4 + type 2 helper T (Th)-cells in response to allergen exposure and these cells are considered mainly responsible for the disease. Thus, it is not surprising that a correlation between CD4 [11][12][13][14][15][16]. But which subset, or subsets are found in asthma?…”

“…Interestingly, it has been shown that CD8 + T-cells can develop this Foxp3-independent suppressive activity only in the absence of alarmins [16]. Thus, this mode of action would promote peripheral tolerance to immunogenic antigens that do not cause tissue damage.…”