No abstract

Genes for peripheral tissue-restricted self-antigens are expressed in thymic and hematopoietic cells. In thymic medullary epithelial cells, self-antigen expression imposes selection on developing autoreactive T cells and regulates susceptibility to autoimmune disease in mouse models. Less is known about the role of self-antigen expression by hematopoietic cells. Here we demonstrate that one of the endocrine self-antigens expressed by human blood myeloid cells, proinsulin, is encoded by an RNA splice variant. The surface expression of immunoreactive proinsulin was significantly decreased after transfection of monocytes with small interfering RNA to proinsulin. Furthermore, analogous to proinsulin transcripts in the thymus, the abundance of the proinsulin RNA splice variant in blood cells corresponded with the length of the variable number of tandem repeats 5 of the proinsulin gene, known to be associated with type 1 diabetes susceptibility. Self-antigen expression by peripheral myeloid cells extends the umbrella of ''immunological self'' and, by analogy with the thymus, may be implicated in peripheral immune tolerance.variable number of tandem repeats ͉ insulin ͉ type 1 diabetes ͉ siRNA ͉ self-antigen T cells with high-avidity receptors for self-antigens are deleted developmentally in the thymus. This central mechanism of immune tolerance appears to depend on the ectopic expression of self-antigens by thymic medullary epithelial cells (1-4). However, in both the mouse (5) and human (6, 7) thymus, self-antigen RNA transcripts or peptide epitopes are also expressed by cells bearing markers of dendritic and monocytic antigen-presenting cells. In human thymus and spleen (6), and more recently in human blood (8), Pugliese and colleagues have described cells with myeloid lineage markers that stain with antibodies to the pancreatic ␤ cell autoantigens in type 1 diabetes [i.e., proinsulin, glutamic acid decarboxylase (GAD), and tyrosine phosphatase-like insulinoma antigen (IA-2)] and transcribe the proinsulin gene. Hematopoietic progenitor cells have been shown to transcribe genes and express proteins for several neural autoantigens, including myelin basic protein (9) and GAD65 (10), and bone marrow-derived cells in extra-pancreatic tissues have been reported to express genes for pancreatic hormones (11). A role for ectopic self-antigen expression in hematopoietic cells was suggested by Zheng et al. (12), who demonstrated activation-induced death of self-reactive T cells in response to bone marrow cells expressing self-antigen.Proinsulin is a key autoantigen that drives pancreatic ␤ cell destruction in type 1 diabetes (13). In the human thymus, proinsulin mRNA abundance correlates with allelism of the variable number of tandem repeats (VNTR) upstream of the proinsulin coding region on chromosome 11 (14, 15), identified as the IDDM2 susceptibility locus for type 1 diabetes (16,17). In addition to abundance of expression, the nature of self-antigen in lymphoid tissues may be important for the acquisition of immune toleranc...

Immune responses to self are kept in check by tolerance mechanisms, including suppression by regulatory T cells (Tregs). The defective generation of Tregs specific for self-antigens may lead to autoimmune disease. We identified a novel population of human CD4^+^ Tregs, characterized by high surface expression of CD52, which is co-generated in response to autoantigen. Blood CD4^+^CD52^hi^ T cells were generated preferentially in response to low-dose autoantigen and suppressed proliferation and interferon-[gamma] production by other T cells. Depletion of resting CD4^+^CD52^hi^ T cells enhanced the T-cell response to autoantigen. CD4^+^CD52^hi^ Tregs were neither derived from nor distinguished by markers of conventional resting CD4^+^CD25^+^ Tregs. In response to the pancreatic islet autoantigens glutamic acid decarboxylase, the generation of CD4^+^CD52^hi^ Tregs was impaired in individuals with and at-risk for type 1 diabetes, compared to healthy controls and individuals with type 2 diabetes. CD4^+^CD52^hi^ Tregs co-generated to self-antigen may therefore contribute to immune homeostasis and protect against autoimmune disease.

No abstract