Self-reactivity controls the functional diversity of naïve CD8+ T cells by co-opting tonic type I interferon

2022-03-11l Hit 4811

Professor Cheol-Heui YUN (Department of Agricultural Biotechnology)

Young-Jun Ju, Sung-Woo Lee, Yoon-Chul Kye, Gil-Woo Lee, Hee-Ok Kim, Cheol-Heui Yun* & Jae-Ho Cho* (Nat. Commun. 2021 Oct 18; 12: 6059.) *Correspondence

Self-reactivity of naïve CD8+ T cells has been reported to  be highly correlated with responsiveness against foreign-antigens, including viruses and intracellular bacteria. However, the precise underlying mechanisms are unclear. Here, the research team of Professor Cheol-Heui YUN (Young-Jun Ju and Yoon-Chul Kye being Ph. D. students at YUN’s lab) collaborated with T cell immunologist, Professor Jae-Ho Cho at Chonnam National University have demonstrated that naïve CD8+ T cells with relatively high self-reactivity are phenotypically more heterogeneous than low self-reactive cells owing to varied responses to type I interferon, resulting in three distinct subsets, CD5loLy6C–, CD5hiLy6C–, and CD5hiLy6C+ cells.

Fig 1. Newly defined classification of heterogenic naïve CD8+ T cell pools and unanswered questions in the present study.

CD5hiLy6C+ cells have shown distinct immunological features compared with CD5loLy6C– and CD5hiLy6C– cells in terms of gene expression profiles and functional properties. Moreover, CD5hiLy6C+ cells have demonstrated more extensive antigen-specific clonal expansion upon viral infection, with enhanced differentiation into terminal effector cells and reduced memory cell generation. On the other hand, CD5loLy6C– cells clearly showed low capacity of clonal expansion with a potential to be maintained as long-term memory cells. Research teams have suggested such immunological features of naïve CD8+ T cell subsets are imprinted by continuous exposure of tonic type I IFN and self-TCR signals at naïve T cells stage. This finding is the first evidence, at the best of our knowledge, that naïve CD8+ T cells would have pre-determined differentiation preferences during their activation. Furthermore, a major factor for such pre-determination is self-reactivity co-option with tonic type I IFN.

Fig 2. Different immunological features among naïve CD8+ T cell subsets through intensity of self-TCR and tonic type I IFN signal.

Collectively, naïve CD8+ T cells continuously co-opt tonic type I IFN signals with varying sensitivity of self-TCR contacts, which in turn, shapes their unique functional properties that sre not same from one subset to another. The consequence of these effects is to broaden and increase the complexity of naïve CD8+ T cell pools with respect to immune responses beyond their TCR specificity and diversity.

This work was published in Nature Communications in 2021.