Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health

Abstract

cal research (2-5), so the need for disease markers that represent islet-damaging or islet-protective events, such as numbers and phenotype of circulating islet autoreactive T cells, has become more urgent.In terms of distinguishing pathological from protective responses, it has been proposed that proinflammatory (type 1) T cell immunity is responsible for islet damage, while humoral (type 2) immunity may be protective, or at least benign (6).These speculations are largely based on studies in animal models, however, and even then the findings have not always been consistent with the hypothesis (7, 8).In addition, it is proposed that naturally arising, regulatory T cell populations are available to curb autoimmune potential (9), but as yet there is no evidence for islet antigen-specific regulatory cell populations existing in humans.Obtaining answers to these key questions has been hampered by technical difficulties, since the constraints on assay design for the detection of islet autoreactive T cells are considerable.Studies can only make use of peripheral blood, in which islet autoreactive T cells are likely to be rare, so assays must be highly sensitive.Ideally, in the context of therapeutic intervention trials using immune modulators, the readout for islet autoreactive T cells should represent a phenotype relevant to ongoing islet inflammation or the restoration of tolerance.Finally, to achieve accurate enumeration of responder cells, assays should avoid in vitro expansion steps.The cytokine enzyme-linked immunosorbent spot (ELISPOT) assay has many of the requisite qualities (10).