TIGIT expression identifies circulating CD38(+) effector T cells with immune regulatory properties whose frequencies at diagnosis predict disease course of paediatric IBD patients

Disease heterogeneity hampers achieving long-term disease remission in inflammatory bowel disease (IBD). Monitoring ongoing tissue-localised regulatory and inflammatory T-cell responses in patient peripheral blood would allow disease classification and empower tailored therapeutic strategies. Previously, we demonstrated that CD38 expression on peripheral blood CD4+ effector (CD4+CD62Lneg) T cells enriches for T cells with specificity for mucosal antigens. This T-cell phenotype allows us to compare CD38+ effector T cells with CD38neg effector T cells, a population that is enriched for cells homing towards the skin. We determined whether regulatory and inflammatory phenotypes of circulating CD38+ effector (CD62LnegCD4+) T cells classify disease activity and disease course in paediatric IBD patients. Flow cytometric analysis was performed on longitudinally followed paediatric IBD patients and age-matched healthy controls. Novel CD38+ effector T-cell-expressed regulatory proteins suitable for disease monitoring were identified by transcriptomics and functionally tested in cultures. In healthy individuals, circulating CD38+ effector T cells had a predominant regulatory component with lower frequencies of IFN γ -secreting T cells, higher frequencies of IL-10-secreting T cells and higher frequencies of inhibitory molecule T-cell immunoglobulin and ITIM domain+ (TIGIT) cells when compared with CD38neg effector T cells. TIGIT expression was stable upon in vitro stimulation and marked CD38+ effector T cells with regulatory properties. In therapy-naïve IBD patients with active intestinal inflammation the predominant regulatory component was lost as evidenced by increased frequencies of activated CD25+CD45RAneg and decreased frequencies of TIGIT+ cells in the circulating CD38+ effector T-cell population. TIGIT percentages lower than 25% prior to treatment discriminated patients with shorter duration of clinical remission demonstrating that the composition of the circulating CD38+ effector T cell population can be used to classify disease heterogeneity in IBD. Compositional changes of the circulating CD38+ effector T cell pool, in particular the frequency of regulatory TIGIT+ cells, classify paediatric IBD patients and predict disease course.