IL-10 signaling in T cells is essential for induction of transplant tolerance

• Published in: The Journal of immunology (1950) 2020-05, Vol.204 (1_Supplement), p.161-161.17
• Main Authors: Lozano, Marcos Iglesias, Bibicheff, Darrel, Chicco, Maria, Brandacher, Gerald, Raimondi, Giorgio
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.204.Supp.161.17

Induction of long term transplant survival by “costimulation blockade” (CoB) regimens is impaired by inflammatory responses. We and others recently revealed new interrelations between inflammatory cytokines and interleukin 10 (IL-10) that alter the signaling outcome of the latter. In this study we investigated the role of IL-10 during transplant tolerance induction. Using a murine full-mismatch skin transplantation model, we showed that IL-10 has a fundamental role in the protective effect of CoB. This tolerizing regimen also failed to be effective in recipient mice with T cell specific unresponsiveness to IL-10, revealing an unexpected important direct modulation of T cells by this cytokine. Accelerated rejection in these transgenic mice correlated with increased accumulation of T cells producing TNF-α, and IFN-γ, and a doubling of IL-17A secreting lymphocytes. We then investigated the mechanism behind modulation of T cells physiology by IL-10. Using in vitro generated rested-effector cells, we show that IL-10 did not reduce their signaling threshold nor their effector functions (cytokine secretion). Moreover, IL-10 did not promote the expression of inhibitory receptors. Instead, we discovered that IL-10 can completely neutralize the TLR-mediated (CD28 independent) costimulation of memory and effector T cells (a largely unexplored phenomenon). We have an ongoing RNAseq analysis to decipher this novel mechanism at the molecular level. Overall, these results highlight the importance of IL-10 signaling for the therapeutic efficacy of CoB. A better understanding of the effects of this cytokine on T cells will reveal targets of strategies to sustain and potentially improve the clinical efficacy of CoB.