Lilin Ye’s group revealed new mechanisms of the longevity of virus-specific memory CD4 T cells
Source:Lilin Ye
On December 23, 2021, a research article entitled “The kinase complex mTORC2 promotes the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis” was published in Nature Immunology. This study led by Dr. Lilin Ye from Army Medical University indicates the kinase complex mTORC2 is critical for the long-term persistence of virus-specific memory CD4 T cells, by preventing the occurrence of ferroptotic cell death.

Immunological memory is the hallmark of adaptive immunity. Memory CD4 and CD8 T cell constitutes the T cell immunological memory, which is the hallmark of the adaptive immunity, empowering host to confer efficient and rapid protection from microbial re-infection. Researches in past decades have made great progress in the investigation of development and maintenance of memory CD8 T cell, however, the underlying mechanisms of CD4 T cell memory is highly elusive. Deciphering the mechanisms of development and maintenance of CD4 T cell immunological memory is a vital and urgent task.

In acute viral infection mouse model using LCMV Armstrong, the researchers found that the deficiency of mTORC2 signaling resulted in significantly decreased population of virus-specific memory CD4 T cells. Additionally, they demonstrated that it is ferroptotic cell death shrinking the memory CD4 T cell pool with mTORC2-deficiency.

The researchers confirmed the phenotype of ferroptosis from various aspects, i.e., flow cytometric analysis of lipid peroxidation (Bodipy C11), ferroptotic transcriptional signature analysis (GSEA), and morphological features (TEM). Furthermore, in vivo administration of lipophilic hydroxyl peroxide radical scavenger (α–Tocopherol) or ferroptosis-specific inhibitor (Liproxstatin-1) efficiently rescued the loss of virus-specific memory CD4 T cells by reducing the accumulation of peroxided lipids. Moreover, by using the GPX4 knockout and overexpression strategy, they pinpoint that mTORC2 signaling promoted the long-term maintenance of virus-specific memory CD4 T cells via inhibiting ferroptosis.

Mechanistically, virus-specific memory CD4 T cells retain tonic mTORC2 signaling upon IL7/IL7R engagement. mTORC2 inactivation resulted in the impaired phosphoylation of downstream AKT and GSK3β kinases, which induced aberrant mitochondrial reactive oxygen species (ROS) accumulation and ensuing ferroptosis-causative lipid peroxidation in virus-specific memory CD4 T cells; furthermore, the disruption of this signaling cascade also inhibited GPX4, a major scavenger of lipid peroxidation. Thus, the mTORC2–AKT–GSK3β axis functions as a key signaling hub to promote the longevity of virus-specific memory CD4 T cells by preventing ferroptosis.

Figure: mTORC2 signaling promotes memory CD4 T cell maintenance.

This research unveiled a critical role of mTORC2-p-AKTSer473-p-GSK3βSer9 signaling axis in prolonging the persistence of antigen-specific memory CD4 T cells by antagonizing ferroptosis. The modulation of this pathway may be employed to improve the long-term efficacies of vaccination or to alleviate certain autoimmune diseases by inducing ferroptotic cell death of pathogenic memory CD4 T cells.

Prof. Lilin Ye from Army Medical University, Prof. Jianqing Xu from Fudan Univeristy and Prof. Zhinan Yin from Jinan University are co-corresponding authors of this paper. Dr. Yifei Wang from Southern Medical University, Dr. Qin Tian, and Dr. Yaxing Hao from Army Medical University are co-first authors. Meanwhile, Wei Yao, Jinjin Lu, and Cheng Chen contributed greatly to this work as postgraduates. This study was funded by the grants from National Key Research Development Plan, National Natural Science Fund for Distinguished Young Scholars, National Natural Science Foundation of China, China Postdoctoral Science Foundation, and Chongqing Special Postdoctoral Science Foundation.