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.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.

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IntroductionNaturally occurring CD4 + CD25 + regulatory (Treg) T cells play a fundamental role in maintaining immune homeostasis [1]. Alterations in the number or functional activity of Treg cells have been observed in several immunological disease states [2]. Furthermore, studies in mice have reported beneficial effects of Treg-cell-based immunotherapies in a wide range of disease models. This has quickly prompted the initiation of early phase clinical Correspondence: Dr. Michael H. Albert e-mail: michael.albert@med.uni-muenchen.de trials in humans with promising preliminary results [3][4][5]. A stringent definition of the human Treg-cell phenotype is, however, a prerequisite for such studies. Therefore, much effort has been put into characterizing human Treg cells based on the expression of specific markers, ideally on the cell surface. In addition to CD25, other surface markers such as CD62L, GITR, LAG-3, and CTLA-4 were identified to be expressed in Treg cells, albeit not exclusively so [6][7][8][9][10]. These markers are also up-regulated in recently activated nonregulatory human T cells, limiting their usefulness as markers [11][12][13]. The same is true for CD127 which was found to be absent on Treg cells but not on conventional T cells. It has recently been shown to be down-regulated upon activation C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 1628 Thomas Magg et al. Eur. J. Immunol. 2012. 42: 1627-1638. These findings cast some shadow on numerous studies using these surface markers to describe the Treg-cell phenotype in human disease [15][16][17]. The identification of one or more dependable identifier molecules could significantly propel Treg-cell research and clinical application forward. The transcription factor forkhead box protein P3 (FOXP3) is considered to be the master regulator for the development and function of Treg cells [18,19]. It is highly expressed in Treg cells and generally accepted as the single best marker to identify Treg cells [19]. But just as the surface markers named above, FOXP3 expression is not Treg cell-specific but is also up-regulated in nonregulatory CD4+ T cells upon activation [20]. Kinetic studies of FOXP3 expression in activated human T cells reveal a transient up-regulation of the protein that is not sufficient to induce a regulatory phenotype in vitro [11]. These findings might suggest a differential function of FOXP3 in activated T cells and in Treg cells. The complex nature of FOXP3 is further highlighted by the presence of different splice variants [20][21][22], whose functions remain largely obscure. One would expect that the cellular functions of FOXP3 are tightly controlled, FOXP3 being such an important molecule for immune homeostasis in general and Treg-cell function in particular. Recently, it has been reported that a substantial subset of murine naturally occurring Treg cells can lose their FOXP3 expression and become auto aggressive, stressing the notion that regulation of FOXP3 expression is an important physiological switch in ...

Transforming growth factor (TGF)-β1 (encoded by TGFB1) is the prototypic member of the TGF-β family of 33 proteins that orchestrate embryogenesis, development and tissue homeostasis. Following its discovery , enormous interest and numerous controversies have emerged about the role of TGF-β in coordinating the balance of pro- and anti-oncogenic properties, pro- and anti-inflammatory effects , or pro- and anti-fibrinogenic characteristics . Here we describe three individuals from two pedigrees with biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy. The proteins encoded by the mutated TGFB1 alleles were characterized by impaired secretion, function or stability of the TGF-β1-LAP complex, which is suggestive of perturbed bioavailability of TGF-β1. Our study shows that TGF-β1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans.