Leong, Y. A. | Search bioRxiv

bioRxiv2024

IL-2 enhances effector function but suppresses follicular localization of CD8+ T cells in chronic infection

Cytotoxic CD8+ T cells, essential in combating viral infections and cancer, become dysfunctional from prolonged antigen exposure. Precursors of exhausted T (TPEX) cells are pivotal in sustaining immune responses in chronic diseases and mediating immunotherapy efficacy. They also control viral infection within B-cell follicles, facilitated by CXCR5 expression. How cytokines regulate TPEX cell fate and follicular entry is not well understood. We reveal that IL-2 treatment enhances CD8+ T cell effector functions in chronic LCMV infection but hinders CXCR5+ TPEX cell formation and infection control within B-cell follicles. Mechanistically, IL-2 suppresses TPEX cell differentiation in a STAT5 and BLIMP1-dependent manner. Using an IL-2 fusion protein targeting CD122, we shifted the differentiation towards CX3CR1+ T cells with increased effector function. Clinical observations with low-dose IL-2 in autoimmune disease confirmed IL-2s inhibitory effect on CXCR5+ TPEX cells, underscoring IL-2s crucial regulatory role and therapeutic potential in modulating TPEX and effector T cell generation.

immunology↗

bioRxiv2022

Trade-Offs Between Hepatic Host Defense and Metabolic Programs Underlie Sex-Biased Diseases

Current concepts in evolutionary medicine propose that trade-offs and mismatches with a shifting environment increase disease risk. While biological sex also impacts disease prevalence, contributions of environmental pressures to sex-biased diseases remain unexplored. Here, we show that sex-dependent hepatic programs confer a robust (~300%) survival advantage for male mice during lethal bacterial infection. The transcription factor BCL6, which masculinizes hepatic gene expression at puberty, is essential for this advantage. However, protection by BCL6 comes at a cost following dietary excess, resulting in overt fatty liver and glucose intolerance in males. Deleting hepatic BCL6 reverses these phenotypes but markedly lowers male fitness during infection, thus establishing a sex-dependent tradeoff between host defense and metabolic systems. We suggest that these tradeoffs, coupled with current environmental pressures, drive metabolic disease in males.

physiology↗