Disparate differentiation between naïve and memory CD8 T cells during persistent antigenic stimulation
Abstract
The adaptive immune system, consisting of humoral and cellular immunity, is highly specific to a particular pathogen and generates immunological memory. Memory cells result in a rapid and robust protective immunity when they reencounter the same microbe. However, it has been previously reported that memory cells quickly disappeared upon persistent viral infection, unlike naïve cells. Furthermore, memory cells mediated impaired anti-tumor activity compared to naïve cells in the adoptive T cell therapy model. However, the underlying mechanism of the defect of memory cells during persistent antigenic stimulation has not been fully understood. In this study, we found that memory CD8 T cells could not generate CXCR5+ progenitor exhausted CD8 T cell subset (Tpex), which is indispensable for maintaining CD8 T cell immunity during persistent antigenic stimulation. We also confirmed that a deficit of memory cells in the generation of Tpex occurred irrespective of the virus or vaccine vehicles to generate memory cells. Memory CD8 T cells highly expressed TCF1, a master regulator for Tpex generation. In addition, memory CD8 T cells upregulated TOX expression, another essential transcription factor for regulating T cell exhaustion, similar to naïve CD8 T cells, suggesting that there was no intrinsic defect of memory CD8 T cells for the generation of Tpex. Of interest, we found that inhibition of type I interferon(IFN-I)-mediated signals, not B7 molecules and IL-2, led to the generation of Tpex by memory CD8 T cells, while the blockade of B7 molecules, IL-2, and IFN-I augmented the population of naïve-derived Tpex cells. Finally, when memory CD8 T cells were transferred into chronically infected mice, they could generate Tpex cells, although the population was smaller than naïve cells. These results suggest that memory T cells are prone to terminally differentiated during persistent antigenic stimulation and have implications for optimizing T cell immunotherapy in chronic infections and cancer.
Optimizing cytokine milieu in adoptive T cell therapy of cancer
Abstract
Adoptive T cell therapy (ACT), a strategy for cancer treatment, has shown impressive therapeutic potential in hematologic cancer and melanoma. Lymphodepletion pre-conditioning, which is generally performed before the adoptive transfer of T cells, enhances the efficacy of ACT by increasing the graft rate of the T cells. However, the function of the transferred T cells is affected by immune-suppressive cells that repopulate after lymphodepletion. We designed a post-conditioning regimen that involves transient treatment with CD4-depleting antibody. In ACT of murine melanoma, the combination of cyclophosphamide pre-conditioning and anti-CD4 post-conditioning significantly enhanced anti-tumor efficacy. The combination regimen accelerated the expansion of CD8+ T cells and increased the proportion of IL-18Rα-high T cell subset which induced strong anti-tumor immune response in an IL-18/TCR signaling dependent manner. Notably, the regimen created a cytokine milieu that was more similar to lymphodepleted condition than to Treg-depleted inflammation milieu. This study demonstrates the clinical relevance of anti-CD4 post-conditioning in ACT and provides insights into the function of IL-18Rα-high CD8+ T cells in cancer immunology.
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