The current data indicate that the character of the inflammatory environment can affect the balance between Teff and Treg cell activation by instructing the maturing DC to adopt a stable propensity to interact with each of these T-cell types. Our results show that in analogy to the previously identified ability of maturing DC to memorize the conditions of their maturation and translate them into different ability to induce the functionally different T-cell responses (14
), maturing DC can also be primed for preferential interaction with the functionally different T-cell subsets.
Although numerous chemokines, including CCL20, CCL22, and CXCL12, respectively, signaling via CCR20, CCR4, and CXCR4, are known to preferentially attract Treg to different tissues (refs. 3
reviewed in ref. 38
), our data show that the ability of human DC to attract FOXP3+
Treg cells is strictly CCR4dependent (), implicating the key role of CCL22, the only DC-produced CCR4 ligand (see ).
Furthermore, our data indicate that PGE2
, including the endogenously produced PGE2
() and the PGE2
produced by tumor tissues (Supplementary Fig. S4
), is a potent inducer of the Treg-attracting propensity of human DCs. In contrast to this common mediator of chronic inflammation (21
), IFNα, a factor produced at the early stages of intracellular infections and known to promote the production of Teff-attracting chemokines (26
), proved to be a potent antagonist of Treg-attracting DC function. Although similar CCL22-antagonistic function has been reported in the case of IFNγ (22
), the factor produced by NK and T cells, the current data indicate that the suppression of Treg recruitment can be also driven by the factors released from directly infected stromal cells at the earliest stages of acute infection, facilitating the early induction of the pathogen-specific immunity.
Interestingly, the IFNα-induced production of CXCL10 (and other CXCR3 ligands; data not shown) was evident within 6 h of DC activation and was terminated following the elimination of the IFNα signal. In contrast, CCL22 induction occurred with substantial delay and was produced at high concentrations over prolonged period of time. This particular kinetics of the PGE2-induced production of CCL22 and the resulting Treg attraction is consistent with the role of PGE2 in preserving tissue homeostasis and limiting the duration of the inflammatory type responses.
The ability of PGE2
to prime DC for elevated attraction of Treg cells adds to the previously postulated ability of this agent to promote the de novo
induction of Treg cells (9
), as well as to its previously defined ability to suppress the functions of Th1-type cells (39
), and to promote the recruitment of Th2 cells (22
). Although the ability of PGE2
to promote the attraction of Tregs is likely to be advantageous in limiting the duration of physiologic immune responses and the associated tissue damage, it is also likely to contribute to the limited effectiveness of responses against PGE2
-overproducing cancers (43
), able to imprint high CCL22-producing function in DC (Supplementary Fig. S4
Importantly, the PGE2
-induced Treg-attracting phenotype persisted in DC even after the removal of PGE2
, with the second wave of the CCL22 production being further elevated after the secondary stimulation of the PGE2
-exposed DC with CD40L. Similarly, the elevated production of CXCL10 by IFNα-matured DC could also be observed following CD40L-mediated restimulation of DCs in the absence of IFNα. This ability of DC to memorize the conditions of their maturation, reflecting them in their subsequent chemokine production, is likely to have implications for the therapeutic use of DC to preferentially activate different T-cell subsets. Although PGE2
-matured DCs have been shown to expand the numbers of FOXP3+
Treg cells in cancer patients (20
), it remains to be seen whether such undesirable effects can be reduced in the clinical trials involving αDC1s or other DC types obtained in the absence of PGE2
In summary, the current data show that the inflammatory factors present during DC maturation imprint the differential ability of mature DC to interact with distinct T-cell subsets. Our data help to explain the hyperactivation of the Treg system in the setting of chronic infections and cancer and facilitate the design of the immunotherapies aimed at the selective activation of the inflammatory versus regulatory type of immune cells.