Funktionelle Differenzierung und Plastizität humaner Th17 Zellen
Final Report Abstract
Th17 cells have emerged as a new T helper cell lineage involved in the clearance of extracellular bacteria and fungi. A dys-regulated Th17 response, however, can induce severe tissue destruction and autoimmunity. Therefore, mechanisms must be in place to shield the host from immune-mediated damage. We demonstrated that human Th17 cells transiently produce the antiinflammatory cytokine IL-10 upon stimulation. Interestingly, IL-10 expression was accompanied by reciprocal down-regulation of IL-17, leading to a functional regulatory Th17 cell phenotype after the peak of the effector response. The ability of Th17 cells to express IL-10 was, however, restricted to certain antigen specificities. Ex vivo isolated C. albicans specific Th17 cells could not produce IL-10 in comparison to S. aureus specific Th17 cells. This was due to differential priming requirements of these Th17 cell subpopulations. IL-1beta instructed naïve T cells to develop into a proinflammatory non-IL10 expressing Th17 cell subset. Th17 cell priming with S. aureus, however, was not IL-1beta dependent, leading instead to the generation of IL-10 producing Th17 cells with self-regulatory activities. Thus, using a novel approach that combines the in vitro priming of naive T cells by whole microbes with the ex vivo analysis of memory T cells, we were able to unmask the existence of two types of Th17 cells that differ in priming requirements, TCR repertoire and function. This approach revealed that IL-1beta is a molecular switch for determining a functional memory for IL-10 expression. This has important consequences for the physiological termination of pro-inflammatory immune responses and the limitation of bystander damage in certain pathogen microenvironments. Targeting IL-1beta early in the differentiation process of Th17 cells (as we demonstrate with IL1ra therapy in CAPS patients) might therefore represent a promising therapeutic strategy to confer anti-inflammatory properties to cellular mediators of autoimmune diseases.
Publications
- Dissecting the human immunologic memory for pathogens. Immunol Rev. 2011 Mar;240(1):40-51
Zielinski CE, Corti D, Mele F, Pinto D, Lanzavecchia A, Sallusto F
