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It takes two (IL-2) to Tango!!!!!




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 mojor 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, the Tregs will create an IL-2 sink
in the microenvironment. This will cause the proliferation and survival of the Tregs. This
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 Tregs cell. Tregs don’t have the capability to produce IL-2.


                                                                                            1
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.




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,




                                                                                        2
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. Sigmoid signal response is a
general principle in different receptor trafficking networks.

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. This is the reason why it takes a while for the Tumors to
begin to shrink because of little proliferation.



                                                                                         3
Although IL-2 deprivation caused apoptosis and little proliferation initially, the effectors
generated under these conditions possessed optimal Effector functions.

So how can we minimize the proliferation of the Tregs which are a subset of CD4+ T-cell
subset?

   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
Although IL-2 deprivation caused apoptosis and little proliferation initially, the effectors
generated under these conditions possessed optimal Effector functions.

So how can we minimize the proliferation of the Tregs which are a subset of CD4+ T-cell
subset?

   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
Although IL-2 deprivation caused apoptosis and little proliferation initially, the effectors
generated under these conditions possessed optimal Effector functions.

So how can we minimize the proliferation of the Tregs which are a subset of CD4+ T-cell
subset?

   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

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It takes two tango 2010

  • 1. It takes two (IL-2) to Tango!!!!! 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 mojor 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, the Tregs will create an IL-2 sink in the microenvironment. This will cause the proliferation and survival of the Tregs. This 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 Tregs cell. Tregs don’t have the capability to produce IL-2. 1
  • 2. 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. 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, 2
  • 3. 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. Sigmoid signal response is a general principle in different receptor trafficking networks. 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. This is the reason why it takes a while for the Tumors to begin to shrink because of little proliferation. 3
  • 4. Although IL-2 deprivation caused apoptosis and little proliferation initially, the effectors generated under these conditions possessed optimal Effector functions. So how can we minimize the proliferation of the Tregs which are a subset of CD4+ T-cell subset? 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
  • 5. Although IL-2 deprivation caused apoptosis and little proliferation initially, the effectors generated under these conditions possessed optimal Effector functions. So how can we minimize the proliferation of the Tregs which are a subset of CD4+ T-cell subset? 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
  • 6. Although IL-2 deprivation caused apoptosis and little proliferation initially, the effectors generated under these conditions possessed optimal Effector functions. So how can we minimize the proliferation of the Tregs which are a subset of CD4+ T-cell subset? 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