Deciphering cholinergic signaling in CD8⁺ T cells during acute and chronic viral infection

Abstract

Acetylcholine is a neurotransmitter of the central and parasympathetic nervous system but can also be produced by immune cells, such as B cell and CD4 T cells. CD8 T cells play an important role in the defense against viral infections and tumor. Here, we deciphered a potential role of cholinergic signaling in effector and memory CD8 T cells during acute viral infection as well as precursor exhausted and exhausted CD8 T cells during chronic viral infection. <br/> In our work, we showed that CD8 T cells express choline acetyltransferase (ChAT), the enzyme that catalyzes the production on acetylcholine, in a T cell receptor-dependent manner. Only antigen-experienced but not naive CD8 T cells can produce acetylcholine. During acute viral infection, ChAT expression peeks during effector phase and decreases dramatically once the virus is cleared. It is partially maintained in memory CD8 T cells. Intriguingly, even though during chronic viral infection, CD8 T cells encounter higher viral load and prolonged antigen-exposure, ChAT expression decreases with progressing T cell exhaustion, indicating an involvement of additional regulatory mechanisms. <br/> Using specific KO mice, we demonstrated that T cell-derived ACh is redundant for effector CD8 T cell differentiation but drives T cell exhaustion. Notably, CD62L⁺ precursor exhausted CD8 T cells as well as conventional dendritic cells type I were increased in the lymph nodes in T cell-specific ChAT KO mice. In line with that, we showed that long term, the ratio of precursor exhausted to exhausted CD8 T cells was increased, indicating reduced T cell exhaustion. <br/> Lastly, we showed that CD8 T cells express the <em>α</em>7 nicotinic receptor. Deletion of a7 nicotinic receptor in virus-specific CD8 T cells impaired the differentiation of short-lived effector cells during acute infection. Strikingly, <em>α</em> nicotinic receptor is crucial for the maintenance of exhausted CD8 T cells as deletion of <em>α</em> nicotinic receptor in CD8 T cells resulted in a loss of exhausted CD8 T cells by day 21 post infection. <br/> Overall, our work suggests a complex role of cholinergic signaling that can both boost and limit CD8 dysfunction during chronic viral infection but has less impact on functional CD8 T cell differentiation during acute viral infection.