Genotype 3 Hepatitis E virus (HEV-3) is an emerging threat for aging population. More than one third of older infected patients develops clinical symptoms with severe liver damage, while others remain asymptomatic. The origin of this discrepancy is still elusive although HEV-3 pathogenesis appears to be immune-mediated. Therefore, we investigated the role of CD8 T cells in the outcome of the
infection in immunocompetent elderly subjects. We enrolled twenty two HEV-3-infected patients displaying similar viral determinants and fifteen healthy donors. Among the infected group, sixteen patients experienced clinical symptoms related to
liver disease while six remained asymptomatic. Here we report that symptomatic
infection is characterized by an expansion of highly activated effector memory CD8 T (EM) cells, regardless of
antigen specificity. This robust activation is associated with key features of early T cell exhaustion including a loss in polyfunctional type-1
cytokine production and partial commitment to type-2 cells. In addition, we show that bystander activation of EM cells seems to be dependent on the inflammatory
cytokines IL-15 and
IL-18, and is supported by an upregulation of the activating
receptor NKG2D and an exuberant expression of T-Bet and T-Bet-regulated genes including
granzyme B and CXCR3. We also show that the inflammatory
chemokines CXCL9-10 are increased in symptomatic patients thereby fostering the recruitment of highly cytotoxic EM cells into the liver in a CXCR3-dependent manner. Finally, we find that the EM-biased immune response returns to homeostasis following viral clearance and disease resolution, further linking the EM cells response to viral burden. Conversely, asymptomatic patients are endowed with low-to-moderate EM cell response. In summary, our findings define immune correlates that contribute to HEV-3 pathogenesis and emphasize the central role of EM cells in governing the outcome of the
infection.