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Autoimmune diseases result from autoantigen-mediated activation of adaptive immunity; intriguingly, autoantigen-specific T cells are also present in healthy donors. An assessment of dynamic changes of this autoreactive repertoire in both health and disease is thus warranted. Here we investigate the physiological versus pathogenic autoreactive processes in the context of Type 1 diabetes (T1D) and one of its landmark autoantigens, glutamic acid decarboxylase 65 (GAD65). Using single cell gene expression profiling and tandem T cell receptor (TCR) sequencing, we find that GAD65-specific true naïve cells are present in both health and disease, with GAD65-specific effector and memory responses showing similar ratios in healthy donors and patients. Deeper assessment of phenotype and TCR repertoire uncover differential features in GAD65-specific TCRs, including lower clonal sizes of healthy donor-derived clonotypes in patients. We thus propose a model whereby physiological autoimmunity against GAD65 is needed during early life, and that alterations of these physiological autoimmune processes in predisposed individuals trigger overt Type 1 diabetes. Autoreactive T cells contribute to the onset of autoimmune diseases but are also detectable in healthy individuals. Here, by examining the dynamics of autoreactive T cell responses to a diabetogenic antigen, the authors show that specific phenotype and T cell receptor repertoire changes are associated with health or disease, with additional cues implicated for this transition. [ABSTRACT FROM AUTHOR]

Type 1 diabetes was one of the earliest disorders to be associated with the phenomenon of autoimmunity and is one of the most studied organ-specific autoimmune diseases at the epidemiologic, immunologic and genetic level. Despite this, and the emergence of a plethora of strategies for trying to intervene in, or prevent the disease, it remains at some distance from being reliably and safely tractable by immunotherapy, a source of great frustration in this research field. In this article we review some of the key concepts that might impact upon this lack of success in the clinic going forward. These include new insights into autoreactive CD4 and CD8 T cell biology and a discussion of the concept of disease heterogeneity as it applies to type 1 diabetes. The onset of disease is characterised by a delicate equilibrium of proinflammatory and regulatory T cells, which we have termed “balanced autoreactive set-point”, and which may be amenable to antigen-specific immunotherapies that alter the rate of disease progression. Advances in the characterization of T cells, especially at the single cell level, could be rewarding, notably from the vantage point of biomarker and surrogate discovery. A better understanding of T cell targeting, autoantigen processing and the β-cell:immune interface is also needed, although access to diseased tissues is a major limitation in this effort. Finally, the existence of disease heterogeneity is an emerging theme in this and other complex immunopathologies, and could be both a blessing (finding the right drug for the right person) and a hindrance (compromising the power of early-stage trials of emerging therapeutics). [ABSTRACT FROM AUTHOR]

We recently demonstrated that the major effector function of neonatal CD4+ T cells is to produce CXCL8, a prototypic cytokine of innate immune cells. In this article, we show that CXCL8 expression, prior to proliferation, is common in newly arising T cells (so-called "recent thymic emigrants") in adults, as well as in babies. This effector potential is acquired in the human thymus, prior to TCR signaling, but rather than describing end-stage differentiation, such cells, whether isolated from neonates or adults, can further differentiate into IFN-γ-producing CD4+ T cells. Thus, the temporal transition of host defense from innate to adaptive immunity is unexpectedly mirrored at the cellular level by the capacity of human innate-like CXCL8-producing CD4+ T cells to transition directly into Th1 cells. [ABSTRACT FROM AUTHOR]