Abstract Naturally occurring CD4 +CD25 +FoxP3 + regulatory T cells (CD25 + Tregs) constitute a specialized population of T cells that is essential for the maintenance of peripheral self-tolerance. The immune regulatory function of CD25 + Tregs depends upon their activation. We found that anti-CD4 antibodies activate the suppressive function of human CD25 + Tregs in a dose-dependent manner.

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We demonstrate that CD4-activated CD25 + Tregs suppress the proliferation of CD4 + and CD8 + T cells, their IL-2 and IFN- production as well as the capacity of CD8 + T cells to re-express CD25. By contrast, anti-CD4 stimulation did not induce suppressive activity in conventional CD4 + T cells. These results identify CD4 as a trigger for the suppressive function of CD25 + Tregs and suggest a possible CD4-mediated exploitation of these cells. Abbreviation: CD25 + Tregs: CD4 +CD25 +Foxp3 + regulatory T cells Introduction CD4 +CD25 +Foxp3 + regulatory T cells (CD25 + Tregs) are a phenotypically and functionally distinct T cell subset that controls immune responses to self and non-self antigens and maintains immune homeostasis.

When activated through the TCR, CD25 + Tregs suppress the proliferation and cytokine production of conventional T cells in an antigen nonspecific, contact-dependent and cytokine-independent process, that has not yet been defined. Simultaneously, activated CD25 + Tregs confer regulatory properties upon suppressed T cells resulting in a second generation of Tregs that modulate immune responses mainly via TGF-β and IL-10,. These observations suggest that the process of tolerance induction by CD25 + Tregs is primarily cell contact-dependent but can involve a secondary contact-independent systemic immunosuppression. Spreading of tolerizing potential to other populations of T cells has been termed infectious tolerance, in analogy to the phenomenon initially described in vivo by transplant immunologists. Originally, the term infectious tolerance describes the induction of long-term tolerance by short-term treatment of mice with non-depleting mAb to CD4 and CD8. Tolerance induced by such treatment is dominant, transferable to naive recipients, and transferred CD4 + T cells have the ability to ‘infect’ naive cells to acquire a tolerant state. Different anti-CD4 mAb-induced tolerogenic CD4 + T cells have been described –.

Whereas some supposedly arise from expanded or activated CD25 + Tregs, others seem to emerge from conventional T cells. However, once the immune system has been perturbed there is no specific surface marker that allows for discrimination between CD25 + Tregs and induced suppressor T cells. Thus, although it is tempting to speculate that CD4 stimulation induced tolerance involves an activation of CD25 + Tregs, it is not yet clear whether these cells can be activated directly by anti-CD4 mAb or whether Tregs are indirectly induced in the course of anti-CD4 treatment.

Moreover, it is generally unknown whether anti-CD4 mAb can alter the function of human CD25 + Tregs. We show here that human CD25 + Tregs can be activated directly by anti-CD4 mAb in a dose-dependent manner. CD4-activated CD25 + Tregs suppressed the proliferation of CD4 + T helper cells, cytokine release and the re-expression of CD25 by CD8 + T cells. These findings suggest a direct activation of CD25 + Tregs in the course of an anti-CD4 treatment. Results Functional activation of human CD25 + Tregs by CD4 stimulation Human peripheral blood contains a heterogeneous population of CD4 +CD25 + T cells that expresses either moderate level of CD25 representing non-regulatory conventional T cells and CD25 high T cells that exhibit regulatory function.

To isolate highly pure CD25 high Tregs we used limiting amounts of CD25-microbeads resulting in CD25 highFoxp3 + T cells that, upon activation, suppressed the proliferation of cocultured conventional CD8 + and CD4 + effector cells (Fig. Notably, CD25 + Tregs depend on activation for their suppressive activity, physiologically through their TCR. In the absence of stimulation, CD25 + Tregs are not suppressive. CD4-activated CD25 + Tregs suppress cytokine synthesis and CD25 re-expression of CD8 + T cells. Top: CD4-activated CD25 + Tregs suppress cytokine synthesis of co-activated CD8 + T cells.

CD25 + Tregs were stimulated with/without anti-CD3 mAb or anti-CD4 mAb (B-F5, 1 µg/mL each) for 48 h. Thereafter, cells were cocultured with T cell-depleted syngeneic PBMC and allogeneic CD8 + T cells. On day 7, alloreactive CD8 + T cells were restimulated with PHA/PMA for 5 h in presence of monensin, fixed and stained with anti-CD8 and cytokine-specific mAb.

The dot plots show gated CD8 + T cells only. Bottom: CD4-activated CD25 + Tregs suppress CD25 re-expression of CD8 + T cells. CD25 + Tregs were stimulated with/without anti-CD3 mAb or anti-CD4 mAb (B-F5, 1 µg/mL each) for 48 h. Thereafter, cells were cocultured with T cell-depleted syngeneic PBMC and allogeneic CD8 + T cells. On day 10, CD8 + T cells were restimulated with allogeneic CD3-depleted PBMC from the same donor as used for primary stimulation and CD25 re-expression of CD8 + T cells was analyzed 24 h after restimulation. A representative result of three is shown.

Numbers indicate percentages of positive cells. CD4-activated CD25 + Tregs phosphorylate ZAP-70 The intracellular part of the CD4 molecule on T cells interacts with the src tyrosine kinase, p56lck. Activation of lck can phosphorylate Tyr 319 within the linker region of ξ-associated protein-70 (ZAP-70), leading to an up-regulation of its activity. Subsequently activated ZAP-70 phosphorylates other downstream substrates.

To verify the activation signal provided by anti-CD4 mAb we analyzed Tyr 319 phosphorylation of ZAP-70 in anti-CD4 stimulated CD25 + Tregs. Similar to anti-CD3, anti-CD4 stimulation resulted in ZAP-70 phosphorylation in CD25 + Tregs (Fig. However, in presence of PP1, a selective inhibitor of src family of tyrosine kinases, CD4-mediated ZAP-70 phosphorylation was blocked. 1 Sakaguchi, S., Fukuma, K., Kuribayashi, K. And Masuda, T., Organ-specific autoimmune diseases induced in mice by elimination of T cell subset.

Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. 2 Belkaid, Y., Piccirillo, C. A., Mendez, S., Shevach, E. And Sacks, D. L., CD4 +CD25 + regulatory T cells control Leishmania major persistence and immunity.

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