Immune responses involve multiple cell-cell interactions within lymphoid tissues, the
trafficking of activated cells to sites of effector function, and the migration of such effector cells within peripheral tissues. To gain a more detailed appreciation of the dynamics of such cell behavior and the relationship between cell dynamics and function, I have put together a series of events that take place during the activation phase of the immune response.
We know based on research that once the CD4+ T cell is activated, within two hours the IL-2 expression and IL-2 receptor are unregulated. IL-2 is secreted 45 minutes into this activation phase.
Experimental work has shown that IL-2 signaling in the first 10 hours is critical for the proliferation decision of T cells in culture. The spacial resolution of the Tregs and the T helper cells during this phase plays a major part in the immune response.
Secreted IL-2 is competed for by the Tregs and the activated CD4+ and CD8+ T-cells. If the Tregs are in close proximity of the T effector cells that are secreting the IL-2, the Tregs will create an IL-2 sink in the microenvironment. This will cause the proliferation and survival of the Tregs which suppresses the effector cell function. The IL-2 sink is where all the IL-2 that is secreted by the T helper cells is adsorbed by the IL-2 receptors on the Treg cells. Tregs don’t have the capability to produce IL-2 so they must scavenge the IL-2 out of the microenvironment of the CD4+ T helper cells. In Treg cells, the IL-2 gene is silenced and IL-2Rα is constitutively expressed through the action of the Treg-lineage-specifying transcription factor FoxP3.
The model proposed by Dr. Dorothea Busse and colleages predicts that the IL-2 secretion rate must exceed a threshold value Theta (θ) to switch IL-2Rα expression to the activated state and permit extensive autocrine IL-2 signaling.
This is just like the three little bears. You need the microenviroment conditions just right to activate T Helper cells.
As you can see in the above diagram, you don’t need high concentration of IL-2, you need spacial distance from one cell to the other. That can be achieved by Anti-CTLA-4 Blockage. By blocking the CTLA-4 receptors, the spacial distance between the T helper cell and the Treg cells increases and it also helps to differentiate the niave CD4+ T cells into Th17 cells.
IL-2 is mainly captured by the Treg cell, whereas autocrine reuptake by the T helper cells predominates when the cells are further apart. So we want to introduce IL-2 before the tumor recruites the Tregs to the Tumor Microenviroment and or when the Treg population is in the contration phase of the CD4+ T-cell cycle.
Cellular signal response is potentially controlled by ratio between ligand (IL-2)
number and surface receptor (IL-2R) number per cell.
Ligand n. An ion, a molecule, or a molecular group that binds to another chemical entity to form a larger complex.
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Suboptimal amounts of IL-2 during priming promoted apoptosis, little proliferation and cell cycling, yet the CD8+ effectors generated produced high levels of cytokines and proliferated autonomously. Although IL-2 deprivation caused apoptosis and little proliferation initially, the effectors generated under these conditions possessed optimal effector functions. This low IL-2 concentration, allows the T help cell to activate and proliferate.
This is the reason why it takes a while for the tumors to begin to shrink because of little proliferation at first. It takes time for the immune system to assemble an army of Cytotoxic T Lymphocytes.
So how can we minimize the proliferation of the Tregs which are a subset of CD4+ T-cell subset without doing a full blown depletion of the CD4+ T-cells?
1. Anti-CTLA-4 Blockage
2. Local IL-21 Promotes the Therapeutic Activity of Effector T cells by
Decreasing Regulatory T Cells Within the Tumor Microenvironment
3. Anti-PD-1 Blockage
4. A combination of the above three.
This is the future of Melanoma Therapy, Combinatorial Therapy.
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B
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