Epidemiological evidence suggests that chronic infections impair immune responses to unrelated pathogens and vaccines. The underlying mechanisms, however, are unclear and distinguishing effects on priming versus development of immunological memory has been challenging. We investigated whether bystander chronic infections impact differentiation of memory CD8(+) T cells, the hallmark of protective immunity against intracellular pathogens. Chronic bystander infections impaired development of memory CD8(+) T cells in several mouse models and humans. These effects were independent of initial priming and were associated with chronic inflammatory signatures. Chronic inflammation negatively impacted the number of bystander CD8(+) T cells and their memory development. Distinct underlying mechanisms of altered survival and differentiation were revealed with the latter regulated by the transcription factors T-bet and Blimp-1. Thus, exposure to prolonged bystander inflammation impairs the effector to memory transition. These data have relevance for immunity and vaccination during persisting infections and chronic inflammation.

Abstract Chronic infections impair immune responses to unrelated pathogens and vaccines but the underlying mechanisms are not clear. We investigated whether bystander chronic infections impact the differentiation of memory CD8 T cells. We demonstrate that diverse chronic viral and parasitic infections substantially impair both the quantity and quality of developing memory CD8 T cells, independently of initial priming. Fully-formed memory CD8 T cells were less susceptible, though not impervious, to the effects of bystander chronic infection, suggesting that the impact of inflammation on memory development is more prominent during the critical period of transitioning from effector to memory. Prolonged induction of type I IFN recapitulated the effects of chronic bystander infection on memory CD8 T cell development, though these effects were independent of IFNAR signaling on the CD8 T cells during chronic infection. However, systemic blockade of IFNAR signaling after the priming phase enhanced the survival and the numerical seeding of the developing memory CD8 T cell pool. In contrast to survival, altered CD8 T cell memory differentiation was regulated by the transcription factors Tbx21 (T-bet) and Prdm1 (Blimp-1), specifically in the post-effector phase. Thus, exposure to chronic bystander infections and inflammation impairs the transition from effector to memory. These results have relevance for immunity and vaccination during persisting infections and chronic inflammation.

Accumulating epidemiological evidence suggests that chronic infections compromise immunity against antigenically unrelated infections, but the underlying mechanisms are unclear. We investigated whether antigenically unrelated “bystander” chronic infections impacted the development of memory CD8 T cells, the hallmarks of protective immunity against intracellular pathogens. We demonstrate that chronic bystander infection and inflammation substantially impair memory CD8 T cell responses in several mouse models with similar changes in non-human primates and in chronically HCV -infected humans. Type I IFN -induced molecular pathways were specifically dysregulated in memory CD8 T cells in inflammatory environments and induction of type I IFN by chronic poly(I:C) administration similarly impaired memory CD8 T cell development and function. Chronic inflammation increased the expression of the proapoptotic protein Bim in bystander CD8 T cells, while inhibiting their IL15-induced rescue from apoptosis ex vivo. Two transcriptional regulators of T cell development, Blimp-1 and T-bet, integrated the effects of inflammatory mediators in impairing optimal memory CD8 T cell development. Thus, exposure to chronic bystander infections deregulates the normal effector to memory CD8 T cell transition. These results have direct relevance concerning current therapeutic approaches and vaccination strategies for patients with persisting infections or chronic inflammatory conditions.