Exogenous interleukin-2 can rescue in-vitro T cell activation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation

Abstract

Capping protein regulator and myosin 1 linker 2 (CARMIL2) deficiency is characterized by impaired T cell activation, which is attributed to defective CD28-mediated co-signaling. Herein, we aimed to analyze the effect of exogenous interleukin (IL)-2 on in-vitro T cell activation and proliferation in a family with CARMIL2 deficiency. This study included four children (one male and three females; aged 2·5-10 years at presentation). The patients presented with inflammatory bowel disease and recurrent viral infections. Genetic analysis revealed a novel homozygous 25-base pairs deletion in CARMIL2. Immunoblotting demonstrated the absence of CARMIL2 protein in all four patients and confirmed the diagnosis of CARMIL2 deficiency. T cells were activated in-vitro with the addition of IL-2 in different concentrations. CD25 and interferon (IFN)-γ levels were measured after 48 h and 5 days of activation. CD25 surface expression on activated CD8 + and CD4 + T cells was significantly diminished in all patients compared to healthy controls. Additionally, CD8 + T cells from all patients demonstrated signifi-cantly reduced IFN-γ production. When cells derived from CARMIL2deficient patients were treated with IL-2, CD25 and IFN-γ production increased in a dose-dependent manner. T cell proliferation, as measured by Cell Trace Violet, was impaired in one patient and it was also rescued with IL-2. In conclusion, we found that IL-2 rescued T cell activation and proliferation in CARMIL2-deficient patients. Thus, IL-2 should be further studied as a potential therapeutic modality for these patients.

Evolution and long‐term outcomes of combined immunodeficiency due to CARMIL2 deficiency

“…All the described mutations were deleterious as they led to undetectable or reduced protein expression (P5) in CD4 + and CD8 + T cells, as measured by flow cytometry (Figure 2B). The current and previously reported mutations were located mostly in the LRR and HD domains, followed by the PH domain, 1,2,[11][12][13][14][15][16][17][18][19][20] and only one mutation in the CBR domain, 28 while mutations in PRR domain have not been identified. Despite undetectable CARMIL2 expression (regardless of mutation location), the clinical presentation varied in severity even between members of the same family.…”

“…All tested patients in our cohort had low Treg and cT FH cells, impaired proliferation in response to anti‐CD28, and low production of IL‐2, IL‐17, and IL‐21 cytokines after CD28 crosslinking. Importantly, the underlying defect was reported to be partially rescued by IL‐2 supplementation 2,15,19 . Compared to other CIDs with defective regulatory T‐cell functions, CARMIL2‐deficient patients exhibit much less autoimmune phenomenon 1,2 .…”

“…Importantly, the underlying defect was reported to be partially rescued by IL-2 supplementation. 2,15,19 Compared to other CIDs with defective regulatory T-cell functions, CARMIL2-deficient patients exhibit much less autoimmune phenomenon. prevent production of autoantibodies due to the inappropriate B-cell co-stimulation especially via ICOS-ICOSL and IL-21/IL-21R, as shown previously in mouse models.…”

Epstein–Barr Virus in Inborn Immunodeficiency—More Than Infection

“…Patients present with low-level EBV-viremia. Interestingly, EBV-LPD or lymphoma has never been observed, instead 20% of the patients (8/44) developed EBV-associated smooth muscle tumors (SMT) [ 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 ]. The mechanisms are still unknown.…”

Clinical & Experimental Immunology: Highlights of 2020

“…This work emphasizes the need for timely diagnosis, optimal management and early referral for curative therapy. Another study from Shamriz et al, Editors' Choice in the June issue [14], showed that interleukin-2 can rescue T cell activation and proliferation in patients with capping protein regulator and myosin 1 linker 2 (CARMIL2) deficiency, which can manifest with immune dysregulation and increased rates of infection. The authors suggest that interleukin-2 should be studied further as a potential therapeutic model for these patients.…”