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Check out the newest work published @Nature from our lab by ...

Check out the newest work published @Nature from our lab by Masao Hashimoto showing that the combination of IL2 and PD1 blockade modifies the CD8 T cell exhaustion program. 1/🧵
We show that this treatment modifies the functional, transcriptional and epigenetic marks of T cell exhaustion. Importantly, we demonstrate that TCF1+ stem-like CD8 T cells are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2
We had previously found that IL2 in combination with a-PDL1 was far better at controlling virus compared to either treatment alone. To study the mechanisms that made this treatment effective, we first wanted to know how the major CD8 T cell subsets present in exhaustion changed
Congenically marked TCF1+ stem-like and Tim3+ CD8 T cells were sorted from chronically infected mice and transferred to infection matched mouse that were treated with anti-PDL1, IL2 or the combination. It was only the stem-like CD8 T-cells that expanded in response to treatment
Treatment with IL2 or combo resulted in a distinct phenotype of cell that was never found in the normal exhaustion setting. These cells (cluster 3) expressed both TCF1 and Granzyme B, had reduced levels of TOX, and had high levels of many cytokine receptors like CD25 and IL18R1
Perhaps most importantly, when we analyzed the epigenetic state of T cells after treatment with IL2, they were far more similar to canonical effector cells. This included closing of the TOX locus and opening of several important cytokine receptor pathways and migratory programs
The expansion of the T cells following treatment with either IL2 or aPDL1 + IL2 resulted in upregulation of CD25. It was only these CD25+ cells that underwent proliferation after treatment (Ki67+)
Finally, the high affinity IL2 alpha receptor was critical for the reprogramming of the T cells to this more effector like state, as IL2 that was engineered to not bind CD25 (IL2v) had no effect on viral control or the transcriptional program of exhausted CD8 cells
These data demonstrate that TCF1+ CD8 T cells are capable of giving rise to more than exhausted daughter cells by manipulation of cytokine signaling. The work highlights the critical role of CD25 in response to IL2 therapy, which has several implications for clinical trials
Thanks to @Nature for their always professional publication process and our collaborators (@HaydnKissick @Maria_Carden1 @RamalingamMD @A_Wieland_PhD @dmcmanus123 @LabScharer + others) for all their hard work and assistance! Ready for any questions!

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