P034 A common IL2RA polymorphism alters natural killer cell immunophenotype and function in Crohn’s disease, with implications for IL-2 based therapy

Abstract Background The single nucleotide polymorphism (SNP) rs61839660 lies within the IL2RA (CD25) intronic enhancer and has been identified as a causal variant in Crohn’s disease (CD), with heterozygote frequency of 16.8% European population. CD25 is high-affinity receptor for IL-2, constitutively expressed on regulatory T cells (Tregs). Low-dose IL-2 (LD-IL2) under investigation IBD, premise that it will expand group tolerising Tregs. However, finding therapeutic dose which activates Tregs without activating effector (Teffs) proved challenging activation CD56dim NK linked to adverse events trial subjects. We have demonstrated risk (T) allele carriers exhibit higher CD4+ cell expression, enhanced pSTAT5 stimulation greater Teff release pro-inflammatory cytokines. sought understand impact immunophenotype function. Methods recruited CD patients homozygous major (CC), or heterozygous (CT) at locus. extracted peripheral blood mononuclear flow-sorted (cytotoxic) CD56bright (regulatory) subsets. Cells were stimulated then stained intracellular pSTAT5. To assess cytotoxicity, rested media either before plating CFSE-labelled K562 target cells. proportion positive dead marker was assessed each condition. Results There no difference phenotype severity between groups, terms age diagnosis, sex distribution, presence perianal requiring surgery. expression significantly CD56Bright CT subjects compared CC (1b). Enhanced also seen CD56Dim cells, though this did not reach statistical significance (1a). concentration required activate 50% STAT5 lower subjects’ those from (21.5IU/ml vs. 132.4IU/ml, p=0.039). cytotoxicity following exposure (1c). Conclusion Our findings suggest responsiveness signalling mediated by increased CD25. hypothesise these would be LD-IL2, through cytotoxicity. results screening entering trials IL-2-based therapy should considered, threshold may lower.