A human immunodeficiency syndrome caused by mutations in CARMIL2

Abstract

Human T-cell function is dependent on T-cell antigen receptor (TCR) and co-signalling as evidenced by immunodeficiencies affecting TCR-dependent signalling pathways. Here, we show four human patients with EBV+ disseminated smooth muscle tumours that carry two homozygous loss-of-function mutations in the CARMIL2 (RLTPR) gene encoding the capping protein regulator and myosin 1 linker 2. These patients lack regulatory T cells without evidence of organ-specific autoimmunity, and have defective CD28 co-signalling associated with impaired T-cell activation, differentiation and function, as well as perturbed cytoskeletal organization associated with T-cell polarity and migration disorders. Human CARMIL2-deficiency is therefore an autosomal recessive primary immunodeficiency disorder associated with defective CD28-mediated TCR co-signalling and impaired cytoskeletal dynamics.

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

“…Previous studies demonstrated impaired T cell activation and effector functions in patients with CARMIL2 deficiencies [4,6]. Indeed, our patients presented with recurrent viral infections.…”

“…The fundamental value of CARMIL2 for immune defense was also recently proven as patients with bi‐allelic CARMIL2 mutations were diagnosed. Although rare, reports of affected patients have recently been accumulating [1,4,6‐12]. CARMIL2 deficiency is characterized by the reduced regulatory T cell (T reg ) counts and impaired T cell activation, which is attributed to a defect in CD28‐mediated co‐stimulation [4,7‐9].…”

CARMIL family proteins as multidomain regulators of actin-based motility

“…Patients lacked regulatory T-cells and suffered from immunodeficiency syndromes similar to those in patients in the studies discussed earlier (Sorte et al , 2016; Wang et al , 2016; Schober et al , 2017). In T-cells isolated from patients, levels of F-actin at the leading edge were decreased and the microtubule network was disorganized.…”

The clinical and mechanistic intersection of primary atopic disorders and inborn errors of growth and metabolism

“…This molecule engages CD28 on the T cell surface to provide this critical second signal. An autosomal recessive loss‐of‐function mutation in capping protein regulator and myosin 1 linker 2 ( CARMIL2 ) encoding RGD, leucine‐rich repeat, tropomodulin and proline‐rich‐containing protein (RLTPR), a scaffolding protein necessary for CD28‐dependent activation of PI3K/PDK1/AKT in human T cells, was shown to cause a combined immunodeficiency . However, these patients also presented with severe atopic dermatitis, food allergy, significant elevations in IgE, allergic asthma, and cold urticaria.…”