Protective Efficacy of Individual CD8+ T Cell Specificities in Chronic Viral Infection.

Specific CD8(+) T cells (CTLs) play an important role in resolving protracted infection with hepatitis B and C virus in humans and lymphocytic choriomeningitis virus (LCMV) in mice. The contribution of individual CTL specificities to chronic virus control, as well as epitope-specific patterns in timing and persistence of antiviral selection pressure, remain, however, incompletely defined. To monitor and characterize the antiviral efficacy of individual CTL specificities throughout the course of chronic infection, we coinoculated mice with a mixture of wild-type LCMV and genetically engineered CTL epitope-deficient mutant virus. A quantitative longitudinal assessment of viral competition revealed that mice continuously exerted CTL selection pressure on the persisting virus population. The timing of selection pressure characterized individual epitope specificities, and its magnitude varied considerably between individual mice. This longitudinal assessment of "antiviral efficacy" provides a novel parameter to characterize CTL responses in chronic viral infection. It demonstrates remarkable perseverance of all antiviral CTL specificities studied, thus raising hope for therapeutic vaccination in the treatment of persistent viral diseases

The alarmin interleukin-33 promotes the expansion and preserves the stemness of Tcf-1⁺ CD8⁺ T cells in chronic viral infection.

T cell factor 1 (Tcf-1) expressing CD8 <sup>+</sup> T cells exhibit stem-like self-renewing capacity, rendering them key for immune defense against chronic viral infection and cancer. Yet, the signals that promote the formation and maintenance of these stem-like CD8 <sup>+</sup> T cells (CD8 <sup>+</sup> SL) remain poorly defined. Studying CD8 <sup>+</sup> T cell differentiation in mice with chronic viral infection, we identified the alarmin interleukin-33 (IL-33) as pivotal for the expansion and stem-like functioning of CD8 <sup>+</sup> SL as well as for virus control. IL-33 receptor (ST2)-deficient CD8 <sup>+</sup> T cells exhibited biased end differentiation and premature loss of Tcf-1. ST2-deficient CD8 <sup>+</sup> SL responses were restored by blockade of type I interferon signaling, suggesting that IL-33 balances IFN-I effects to control CD8 <sup>+</sup> SL formation in chronic infection. IL-33 signals broadly augmented chromatin accessibility in CD8 <sup>+</sup> SL and determined these cells' re-expansion potential. Our study identifies the IL-33-ST2 axis as an important CD8 <sup>+</sup> SL-promoting pathway in the context of chronic viral infection