PRIMARY immunodeficiency diseases are a heterogeneous group of disorders resulting from intrinsic defects of the immune system.¹ They are frequently associated with repeated bacterial, fungal, or viral infections and may be caused by defects in organs (thymus), cells (B lymphocytes and phagocytes), or molecules (immunoglobulins, complement, adhesion receptors, and enzymes) of the immune system. Primary immunodeficiencies involving T lymphocytes or T-cell–specific molecules have only recently begun to be recognized, and thus children with recurrent infections due to faulty T-lymphocyte function may be given an incorrect diagnosis because of the lack of suitable laboratory tests.² Understanding of T-cell physiology has lagged behind that of B-cell or phagocyte physiology; no genetic defect causing primary T-cell immunodeficiency has yet been characterized.

The thymus produces γδ T cell subsets making either IFN-γ or IL-17. Silva-Santos and colleagues show that TCR signal strength within specific developmental windows is a major determinant of the generation of these γδ T cell subsets. The mouse thymus produces discrete γδ T cell subsets that make either interferon-γ (IFN-γ) or interleukin 17 (IL-17), but the role of the T cell antigen receptor (TCR) in this developmental process remains controversial. Here we show that Cd3g+/− Cd3d+/− (CD3 double-haploinsufficient (CD3DH)) mice have reduced TCR expression and signaling strength on γδ T cells. CD3DH mice had normal numbers and phenotypes of αβ thymocyte subsets, but impaired differentiation of fetal Vγ6+ (but not Vγ4+) IL-17-producing γδ T cells and a marked depletion of IFN-γ-producing CD122+ NK1.1+ γδ T cells throughout ontogeny. Adult CD3DH mice showed reduced peripheral IFN-γ+ γδ T cells and were resistant to experimental cerebral malaria. Thus, TCR signal strength within specific thymic developmental windows is a major determinant of the generation of proinflammatory γδ T cell subsets and their impact on pathophysiology.

Heterotrimers composed of B cell CLL/lymphoma 10 (BCL10), mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and caspase recruitment domain–containing (CARD) family adaptors play a role in NF-κB activation and have been shown to be involved in both the innate and the adaptive arms of immunity in murine models. Moreover, individuals with inherited defects of MALT1, CARD9, and CARD11 present with immunological and clinical phenotypes. Here, we characterized a case of autosomal-recessive, complete BCL10 deficiency in a child with a broad immunodeficiency, including defects of both hematopoietic and nonhematopoietic immunity. The patient died at 3 years of age and was homozygous for a loss-of-expression, loss-of-function BCL10 mutation. The effect of BCL10 deficiency was dependent on the signaling pathway, and, for some pathways, the cell type affected. Despite the noted similarities to BCL10 deficiency in mice, including a deficient adaptive immune response, human BCL10 deficiency in this patient resulted in a number of specific features within cell populations. Treatment of the patient’s myeloid cells with a variety of pathogen-associated molecular pattern molecules (PAMPs) elicited a normal response; however, NF-κB–mediated fibroblast functions were dramatically impaired. The results of this study indicate that inherited BCL10 deficiency should be considered in patients with combined immunodeficiency with B cell, T cell, and fibroblast defects.

Naturally occurring regulatory T cells (Treg) express high levels of glucocorticoid-induced tumour necrosis factor receptor (GITR). However, studies of the role of GITR in Treg biology has been complicated by the observation that upon activation effector CD4⁺ T (Teff) cells also express the receptor. Here, we dissect the contribution of GITR-induced signaling networks in the expansion and function of FoxP3⁺ Treg. We demonstrate that a high-affinity soluble Fc-GITR-L dimer, in conjugation with αCD3, specifically enhances in vitro proliferation of Treg, which retain their phenotypic markers (CD25 and FoxP3) and their suppressor function, while minimally affecting Teff cells. Furthermore, Fc-GITR-L does not impair Teff susceptibility to suppression, as judged by cocultures employing GITR-deficient and GITR-sufficient CD4⁺ T-cell subsets. Notably, this expansion of Treg could also be seen in vivo, by injecting FoxP3-IRES-GFP mice with Fc-GITR-L even in the absence of antigenic stimulation. In order to test the efficacy of these findings therapeutically, we made use of a C3H/HeJ hemophilia B-prone mouse model. The use of liver-targeted human coagulation factor IX (hF.IX) gene therapy in this model has been shown to induce liver toxicity and the subsequent failure of hF.IX expression. Interestingly, injection of Fc-GITR-L into the hemophilia-prone mice that were undergoing liver-targeted hF.IX gene therapy increased the expression of F.IX and reduced the anticoagulation factors. We conclude that GITR engagement enhances Treg proliferation both in vitro and in vivo and that Fc-GITR-L may be a useful tool for in vivo tolerance induction.

INFANTS with severe combined immunodeficiency usually become ill in the first few months of life.¹ Although growth and development proceed normally for a few months, length and weight gain cease, and failure to thrive becomes a striking feature of the disorder.¹ Most affected infants have profound lymphopenia with a specific deficiency in the mature T-cell subset. Although patients with severe combined immunodeficiency share a common clinical picture, the underlying T-cell deficit is heterogeneous. One subtype of severe combined immunodeficiency is associated with the absence of the development of thymocytes that express any thymus-specific antigens (CD3, CD4, CD6, and CD8). In . . .