"Deletion of Trib1 during chronic infection improves viral-specific T cell responses by diverting T cell differentiation away from terminal exhaustion"

Susan McClory, MD, PhD, Oishi Bardhan, Kelly Rome, PhD, Martha Jordan, PhD and Warren Pear, MD, PhD

The ability of T cells to clear chronic infections or cancer is often limited because they become exhausted and lose robust effector function. We discovered that conditional deletion (cKO) of Trib1 from all T cells during chronic LCMV infection (clone 13) leads to decreased viral burden and improved CD8+ and CD4+ effector function. These changes are accompanied by an expansion of CD8+CX3CR1+KLRG1+ effector-like exhausted T cells (Tex) in Trib1 cKO compared to wildtype (WT) mice as well as persistence of a CD8+CX3CR1+KLRG1- transitional Tex subset, previously shown to be critical for viral control. Expansion of Trib1 cKO CD8+CX3CR1+KLRG1+ effector-like cells occurs at the expense of CD101+PD1+CD69+CD39+ cells, a short-lived population of terminally exhausted T cells. These findings suggest that when Trib1 is deleted from T cells during chronic infection, the pathway of terminal exhaustion is suppressed in favor of a KLRG1+ effector-like cell fate. Next, we used Trib1 cKO P14 mice which contain an LCMV-specific MHC class I-restricted TCR to study the CD8-intrinsic effect of Trib1 deletion during chronic infection. When Trib1 cKO P14 cells are adoptively transferred into infected WT recipients, they generate a higher frequency of CX3CR1+KLRG1+ effector-like Tex cells but produce similar amounts of IFN compared to co-transferred WT P14 cells. These data indicate that some effects of Trib1 deletion during chronic infection are CD8-intrinsic whereas others depend on CD4+ T cells. Finally, we found that Trib1 cKO during chronic infection can augment anti-PDL1 blockade to improve viral clearance. Thus, Trib1 signaling plays an important role during T cell exhaustion, and Trib1 may be a novel target for improving T cell function during chronic viral infection and cancer.