Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autosomal recessive disease caused by mutations in the AIRE gene. Here we have produced knock-out mice for the Aire gene. The Aire-/- mice develop normally; however, autoimmune features of APECED in Aire-/- mice are evident, including multiorgan lymphocytic infiltration, circulating autoantibodies and infertility. The distribution of B and T cells and thymic maturation as well as activation of T cells appear normal, while the TCR-Vbeta repertoire is altered in peripheral T cells of Aire-/- mice. When mice are challenged with immunization, the peripheral T cells of Aire-/- mice have a 3-5-fold increased proliferation. These findings suggest that the Aire gene is not necessary for normal T cell education and development, while a defect in immune response detected in challenged Aire-/- mice underlines the crucial role of AIRE/Aire in maintaining homeostatic regulation in the immune system.

Homeostatic proliferation of naive T cells transferred to T cell-deficient syngeneic mice is driven by low-affinity self-MHC/peptide ligands and the cytokine IL-7. In addition to homeostatic proliferation, a subset of naive T cells undergoes massive proliferation in chronically immunodeficient hosts, but not in irradiated normal hosts. Such rapid T cell proliferation occurs largely independent of homeostatic factors, because it was apparent in the absence of IL-7 and in T cell-sufficient hosts devoid of functional T cell immunity. Strikingly, immunodeficient mice raised under germfree conditions supported only slow homeostatic proliferation, but not the marked T cell proliferation observed in conventionally raised immunodeficient mice. Thus, polyclonal naive T cell expansion in T cell-deficient hosts can be driven predominantly by either self-Ags or foreign Ags depending on the host’s previous state of T cell immunocompetency.

Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral problem afflicting 5-10% of children and adolescents and persisting into adulthood in 30-50% or more of cases.1,2 Family, twin, and adoption studies suggest genetic factors contribute to ADHD and symptoms of inattention, impulsivity, and hyperactivity.3-5 Because stimulant intervention is effective in reducing ADHD symptoms in about 70-80% of cases, molecular genetic investigations of genes involved in dopamine regulation are currently underway by many groups.6-8 In a case control study of the dopamine D4 receptor gene (DRD4) and ADHD, La Hoste and colleagues 9 found an increase of a 7-repeat variant of a 48-bp VNTR in exon 3 10 among ADHD subjects compared to controls. Swanson and colleagues 11 replicated this finding in a sample of 52 ADHD probands and their biological parents using a haplotype relative risk analysis. Here, we describe linkage investigations of the VNTR and ADHD in affected sibling pair (ASP) families and singleton families using both the transmission disequilibrium test (TDT)12 and a mean test of identity-bydescent (IBD) sharing. Using the TDT in the total sample, the 7 allele is differentially transmitted to ADHD children (P = 0.03) while the mean test revealed no evidence of increased IBD sharing among ASPs. In the current sample, the 7 allele attributes a 1.5-fold risk for developing ADHD over non-carriers of the allele estimated under a model described by Risch and Merikangas.13

In conditions of T lymphopenia, interleukin (IL) 7 levels rise and, via T cell receptor for antigen–self–major histocompatibility complex (MHC) interaction, induce residual naive T cells to proliferate. This pattern of lymphopenia-induced “homeostatic” proliferation is typically quite slow and causes a gradual increase in total T cell numbers and differentiation into cells with features of memory cells. In contrast, we describe a novel form of homeostatic proliferation that occurs when naive T cells encounter raised levels of IL-2 and IL-15 in vivo. In this situation, CD8+ T cells undergo massive expansion and rapid differentiation into effector cells, thus closely resembling the T cell response to foreign antigens. However, the responses induced by IL-2/IL-15 are not seen in MHC-deficient hosts, implying that the responses are driven by self-ligands. Hence, homeostatic proliferation of naive T cells can be either slow or fast, with the quality of the response to self being dictated by the particular cytokine (IL-7 vs. IL-2/IL-15) concerned. The relevance of the data to the gradual transition of naive T cells into memory-phenotype (MP) cells with age is discussed.

Aging is associated with a gradual loss of naïve T cells and a reciprocal increase in the proportion of memory T cells. While reduced thymic output is important, age-dependent changes in factors supporting naïve T cells homeostasis may also be involved. Indeed, we noted a dramatic decrease in the ability of aged mice to support survival and homeostatic proliferation of naïve T cells. The defect was not due to a reduction in IL-7 expression, but from a combination of changes in the secondary lymphoid environment that impaired naïve T cell entry and access to key survival factors. We observed an age-related shift in the expression of homing chemokines and structural deterioration of the stromal network in T cell zones. Treatment with IL-7/mAb complexes can restore naïve T cell homeostatic proliferation in aged mice. Our data suggests that homeostatic mechanisms that support the naïve T cell pool deteriorate with age.