P036. Polyfunctionality of human gut-homing CD4 T cells
A.N. Hegazy, A. Datsi, H. Uhlig, F. Powrie, John Radcliffe Hospital, Translational Gastroenterology Unit, Oxford, United Kingdom
The gastrointestinal tract represents one of the most challenging sites for the immune system as immune cells must be able to mount an efficient response to invading pathogens while living peacefully with the diverse commensal microbiota. A permanent disturbance of this delicate balance can lead to the development of inflammatory bowel disease (IBD).
CD4+ T cells can differentiate into a variety of effector subsets, including classical Th1 cells and Th2 cells, the more recently defined Th17 cells, follicular helper T (Tfh) cells, Th9, Th22 and induced regulatory T (iTreg) cells. Differentiation into distinct T cells subsets has been considered to be a unidirectional, irreversible event. However accumulating evidence suggests that there is plasticity amongst differentiated CD4+ T cells, allowing them to acquire functional additional properties that allow adaption to environmental challenges.
CD4+ T cells are found in abundance in mucosal tissues of the gut in healthy individuals under non-inflammatory conditions. Many of these cells produce IL-17 upon TCR stimulation and may promote host protective immunity and intestinal homeostasis. Knowledge on the plasticity and polyfunctionality of gut-homing CD4+ T cells is limited.
To access the functional characteristics of circulating mucosal CD4 T cells, mucosal CD4+ T cells were identified and isolated according to integrin apha4 beta7 expression. Expression of activation markers and others, including homing, chemokine and cytokine receptors as well as expression of cytokines and transcription factors was performed using multicolour flow cytometric analysis.
In healthy individuals alpha4 beta7+ CD4 T cell expressed several chemokine receptors including CCR4, CCR6, CCR7 and CCR9. The majority of alpha4 beta7+ CD4 T cells expressed high amounts of IFN-gamma, TNF-alpha and IL-2. However IFN-gamma was co-expressed with several other non-classical Th1 cytokines including IL-4, IL-13 as well as IL-17 and IL-22. In addition, the alpha4 beta7+ CD4+ T cells expressed high levels of Th1 lineage-specifying transcription factors as T-bet and Eomesodermin. Remarkably alpha4 beta7+ IFN-gamma+ T-bet+ CD4+ T cells co-expressed RORgt and GATA-3.
Taken together, our findings provide new evidence for the polyfunctionality of gut-homing CD4+ T cells, characterised by co-expression of Th1, Th2 and Th17 characteristic cytokines and transcription factors. However how this polyfunctionality is disturbed during intestinal inflammation, remains unknown.