Foxp3+CD4+ regulatory T cells (Tregs) are crucial in maintaining self-tolerance and limiting immune responses to pathogens. Shifting the sensitive balance between Tregs and effector T cells requires extensive knowledge of the homeostatic properties of the different T cell populations. For the investigation of Treg homeostatic expansion, we introduce in this study novel BAC transgenic mice, designated Foxp3.LuciDTR, coexpressing enhanced GFP, luciferase for bioluminescence imaging of Tregs, and the diphtheria toxin receptor (DTR) for specific ablation of Tregs. Of several founder lines, Foxp3.LuciDTR-4 mice displayed ∼95% Treg depletion following injection of DT, resulting in activation of conventional CD4+ T cells, probably due to lack of control by Tregs. In contrast, Foxp3.LuciDTR-3 mice displayed only ∼70% Treg depletion without concomitant activation of CD4+ T cells and represented, therefore, a suitable model to study Treg homeostasis in an environment where other T cell populations were not altered. After depletion, the Treg compartment recovered to its original size in ∼2 wk. This recovery was mediated in a thymus-independent fashion by homeostatic proliferation of the surviving, nondepleted Tregs. The proliferating Tregs acquired an activated phenotype and maintained their suppressive capacity. Studies involving DT-mediated depletion of dendritic cells in CD11c.DOG mice showed that dendritic cells were required for optimal Treg homeostasis. In addition, IL-2 was identified as an essential factor for homeostatic recovery of the Treg compartment. These results show that Treg homeostasis is specifically regulated by the size of the Treg compartment and is independent of proliferation of conventional T cells.
There are a number of factors that hamper immunotherapy of cancer. For example, tumors exhibit an aberrant vasculature that appears to form a barrier against T-cell infiltration. Another major obstacle is created by Treg. So far, conventional depletion of Treg with anti-CD25 antibodies, which eliminate only 70% of Treg, has failed to significantly reduce the growth of established tumors. Using Foxp3.LuciDTR-4 mice, we show here that 90-95% Treg depletion resulted in complete regression of large established tumors, whereas 70% depletion was ineffective. The extensive Treg depletion induced a number of processes that are critical for tumor rejection, including activation of tumorspecific CD81 T cells and enhanced infiltration of these cells into the tumor. The precise mechanism of enhanced infiltration is not known, but normalization of the tumor vasculature is assumed to assist infiltration. Indeed, we observed that 90% Treg depletion caused normalization of the tumor vasculature as indicated by a reduction in leakiness and the number of dilated vessels. These results suggest that for clinical immunotherapy of cancer, it would be desirable to have reagents that allow high-level depletion of Treg, which, in conjunction with treatment modalities such as vaccination, may concomitantly increase T-cell activation and infiltration.Key words: Immunotherapy . Treg . Tumor immunology Supporting Information available online IntroductionGrowing evidence from various malignant entities including melanoma, colorectal, ovarian, cervical, hepatocellular, gastric and urothelial carcinoma indicates that an increased number of tumor infiltrating lymphocytes correlates with favorable disease course and longer survival [1][2][3][4][5][6][7][8][9]. A major obstacle for infiltration appears to be the tumor endothelial barrier. Neoangiogenesis of blood vessels is necessary for tumor survival, but the resulting tumor vasculature usually displays an abnormal architecture characterized by dilated and fragile vessels resulting in leakiness, hypoxia, acidosis and high interstitial pressure [10,11]. Interestingly, normalization of the tumor vasculature by experimental manipulation leads to increased infiltration and tumor destruction [12]. Thus, normalization of the tumor vasculature emerges as a novel and promising approach for immunotherapy. Several studies have attempted to interfere with the growth of mouse transplantation tumors by PC-61 monotherapy. Usually an effect on tumor growth has been observed only in prophylactic settings when Treg were depleted before or no later than 2 days after tumor inoculation, whereas PC-61-mediated Treg depletion in animals carrying established tumors had generally no or only little effect on tumor growth [25][26][27][28]. Significant therapeutic success was only observed when complex combinatorial approaches were applied such as total body irradiation combined with adoptive T-cell transfer and vaccination [29], and additional treatment with anti-PDL1 antibody [30], but usually mice were treated when tu...
Dendritic cells (DCs) are key components of the adaptive immune system contributing to initiation and regulation of T cell responses. T cells continuously scan DCs in lymphoid organs for the presence of foreign antigen. However, little is known about the functional consequences of these frequent T cell-DC interactions without cognate antigen. Here we demonstrate that these contacts in the absence of foreign antigen serve an important function, namely, induction of a basal activation level in T cells required for responsiveness to subsequent encounters with foreign antigens. This basal activation is provided by self-recognition of MHC molecules on DCs. Following DC depletion in mice, T cells became impaired in TCR signaling and immune synapse formation, and consequently were hyporesponsive to antigen. This process was reversible, as T cells quickly recovered when the number of DCs returned to a normal level. The extent of T cell reactivity correlated with the degree of DC depletion in lymphoid organs, suggesting that a full DC compartment guarantees optimal T cell responsiveness. These findings indicate that DCs are specialized cells that not only present foreign antigen, but also promote a "tonic" state in T cells for antigen responsiveness.antigen sensitivity | diphtheria toxin receptor | T cell reactivity
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