Induced Regulatory T Cells Superimpose Their Suppressive Capacity with Effector T Cells in Lymph Nodes via Antigen-Specific S1p1-Dependent Egress Blockage

Abstract

Regulatory T cells (Tregs) restrict overexuberant lymphocyte activation. While close proximity between Tregs and their suppression targets is important for optimal inhibition, and literature indicates that draining lymph nodes (LNs) may serve as a prime location for the suppression, signaling details orchestrating this event are not fully characterized. Using a protocol to enable peripheral generation of inducible antigen-specific Tregs (asTregs) to control allergen-induced asthma, we have identified an antigen-specific mechanism that locks asTregs within hilar LNs which in turn suppresses airway inflammation. The suppressive asTregs, upon antigen stimulation in the LN, downregulate sphingosine-1-phosphate receptor 1 egress receptor expression. These asTregs in turn mediate the downregulation of the same receptor on incoming effector T cells. Therefore, asTregs and effector T cells are locked in these draining LNs for prolonged interactions. Disruption of individual steps of this retention sequence abolishes the inflammation controlled by asTregs. Collectively, this study identifies a new requirement of spatial congregation with their suppression targets essential for asTreg functions and suggests therapeutic programs via Treg traffic control.

Precise Spatiotemporal Interruption of Regulatory T-cell–Mediated CD8+ T-cell Suppression Leads to Tumor Immunity

“…In reality, many of the suppressive mechanisms applicable for CD4 þ T cells may also be at work for CD8 þ T cells. In our previous work, we reported that in an asthma model, peripherally induced Tregs by a vaccine regimen blocked CD4 þ T-cell function via surface downregulation of S1P1 (32). In this report, we found that a similar regulation of CD8 þ T cells: Tregs migrating into TDLNs from the tumor downregulated S1P1 expression on these cells.…”

“…Treg migration to these sites may be a key step for easy access to this cytokine (31). However, more and more reports indicate that lymphoid tissues are an important, if not the key, location for Tregs to mediate their suppression (19,32).…”

Improving Tumor Retention of Effector Cells in Adoptive Cell Transfer Therapies by Magnetic Targeting

“…Alteration in S1PR1 expression in T cells could therefore limit the capacity of adoptively transferred cells to exit the LN they infiltrated. Furthermore, it has also been described that antigen-specific regulatory T cells exert their immunosuppressive action in the LNs by promoting, among other things, a decrease in the expression of S1P1R in effector T cells, thereby trapping these cells in the LN [180]. Evaluating the expression of S1PR1 and of other chemokine receptors, such as CCR7 [181], that control T cell migration in adoptively transferred cells would therefore be useful to optimize the migratory profile of transferred MNP-loaded T cells, so that their retention in the tumor is not only promoted by the EMF but also by biological factors such as chemokines.…”

Deubiquitinase as Potential Targets for Cancer Immunotherapy

“…Activation of antigen-specific T cell response is critical for the treatment of cancer and viral diseases [18][19][20][21]. The activated antigen specific effector T cells could migrate into inflammation or tumor deposits through lymph node [22]. Therefore, modulation of immune response could benefit the treatment of cancer immunotherapy [23].…”