Abstract
T cell anergy is a common mechanism of T cell tolerance. However, although anergic T cells are retained for longer time periods in their hosts, they remain functionally passive. Here, we describe the induction of anergic CD4+ T cells in vivo by intravenous application of high doses of antigen and their subsequent conversion into suppressive Foxp3- IL-10+ Tr1 cells but not Foxp3+ Tregs. We describe the kinetics of up-regulation of several memory-, anergy- and suppression-related markers such as CD44, CD73, FR4, CD25, CD28, PD-1, Egr-2, Foxp3 and CTLA-4 in this process. The conversion into suppressive Tr1 cells correlates with the transient intracellular CTLA-4 expression and required the restimulation of anergic cells in a short-term time window. Restimulation after longer time periods, when CTLA-4 is down-regulated again retains the anergic state but does not lead to the induction of suppressor function. Our data require further functional investigations but at this stage may suggest a role for anergic T cells as a circulating pool of passive cells that may be re-activated into Tr1 cells upon short-term restimulation with high and systemic doses of antigen. It is tentative to speculate that such a scenario may represent cases of allergen responses in non-allergic individuals.
Highlights
T cell tolerance mechanisms include the induction of T cell anergy, T cell deletion and regulatory T cell (Treg) functions
Anergic T cells can be induced in vivo by intravenous injection of high dose antigen [14,15,16] but a characteristic phenotype of anergic T cells is still controversially discussed due to the lack of specific surface markers
Anergy can be induced in vivo by a single intravenous injection of high dose antigen and repetitive administration of antigen can induce IL-10 production in these cells [14,15,16, 19]
Summary
T cell tolerance mechanisms include the induction of T cell anergy, T cell deletion and regulatory T cell (Treg) functions. A functional or active role for anergic T cells in tolerance has not been defined. Most experimental settings to induce T cell anergy in vitro, reported defective IL-2 production and impaired proliferation upon TCR restimulation with or without CD28 costimulation [4,5,6]. This so-called in vitro clonal T cell anergy could be reverted to proliferation by addition of high doses of IL-2 since anergic T cell clones
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