Understanding the impact of IL2RA polymorphism on immunophenotype and response to therapy in IBD

Jennie Clough1,2,3, Rimma Goldberg1, Luke Roberts1, Jeni Sanchez, Peter Irving1,2, Graham Lord1
The single nucleotide polymorphism (SNP) rs61839660 lies within the IL2RA intronic enhancer and has been identified as a causal variant in Crohn’s disease (CD), with a heterozygote frequency of 16.8% in a European population. In collaboration with the NIHR IBD Bioresource, we obtained whole blood samples from CD patients and healthy controls homozygous minor allele (TT), homozygous major allele (CC), or heterozygous (CT) at the rs61839660 locus.
We have demonstrated that risk (T) allele carriers exhibit higher CD4+ T cell CD25 expression, with evidence of a gene-dose effect. Risk allele carriers also show enhanced pSTAT5 activation on stimulation with IL-2, and heterozygotes exhibited enhanced CD4+ effector T cell (Teff) release of pro-inflammatory cytokines in response to TCR stimulation compared to CC subjects. In recent work, we have also found enhanced CD25 expression on natural killer (NK) cell subsets and enhanced cytotoxicity of CD56Dim NK cells in carriers of the risk allele.
Taken together, our findings suggest that risk allele carriers have enhanced responsiveness to IL-2 signalling mediated by increased expression of CD25. We hypothesise that these subjects would be at greater risk of adverse events on exposure to low-dose IL-2, which is currently being trialled in both ulcerative colitis (UC) and CD, through activation of effector cell populations. Our current research is focused on examining the potential in vitro of basiliximab (a monoclonal antibody to CD25) and tofacitinib (Jak1/3 inhibitor) as personalised therapeutic options for carriers of the rs61839660 risk allele. This work is complementary to the ongoing MRC-funded TRIBUTE trial of autologous Treg therapy in CD, which is open for recruitment.

Affiliations:
1. LORD Lab, King’s College London
2. Guy’s and St Thomas’ NHS Foundation Trust
3. NIHR Biomedical Research Centre, Guy’s Hospital, London