The Treg/Th17 Cell Balance: A New Paradigm for Autoimmunity

Abstract

Regulatory T cells and T helper 17 cells are two recently described lymphocyte subsets with opposing actions. In this review, we discuss the mechanisms that promote development of these cells from common precursors and the specific factors that impact their cell numbers and function. Altered regulation of this key developmental checkpoint may contribute to the pathophysiology of autoimmune diseases by tipping the balance toward inflammation. We also present recent findings that suggest how the equilibrium between regulatory T cells and proinflammatory T helper subsets might be pharmacologically restored for therapeutic benefit. (Pediatr Res 65: 26R-31R, 2009) T he recent discovery of two novel subsets of CD4 ϩ T lymphocytes has led to a paradigm shift in the understanding of how autoimmune responses are both mediated and regulated. One of these cell subsets, CD4 ϩ T helper 17 (Th17) lymphocytes, is a key effector cell in rodent models of human diseases including collagen arthritis and experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. A second CD4 ϩ T lymphocyte subset, termed regulatory T (T reg ) cells, is essential for dominant immunologic tolerance. Surprisingly, both Th17 and T reg cells can develop from naïve CD4 ϩ T cell precursors under the influence of the same cytokine, transforming growth factor ␤1 (TGF␤1). In this review, we discuss the ontogeny of T reg and Th17 cells, as well as their known immune functions. We present the hypothesis that certain forms of autoimmunity may result when CD4 ϩ T cell differentiation is biased away from T reg cells and toward the Th17 cell phenotype. Finally, we discuss ways that the Th17/T reg cell balance might be modified to restore immune homeostasis, resulting in therapeutic benefit in autoimmune conditions. Regulatory T Lymphocytes CD4ϩ lymphocytes with suppressor properties have been known to exist for many years. However, the central role of CD4 ϩ CD25 ϩ T reg cells expressing the transcription factor forkhead box protein 3 (Foxp3) in immune regulation was initially disclosed by studies involving the inbred Scurfy mouse strain. In these animals, frameshift mutations in Foxp3 transmitted by X-linked inheritance result in a fatal syndrome of extensive immune activation, leading to oversecretion of numerous cytokines and multiorgan infiltration by inflammatory cells (1). Orthologous mutations were shown to be responsible for the human condition immune dysregulationpolyendocrinopathy-enteropathy-X-linked (2-4). Foxp3 gene transfer to CD4 ϩ CD25 Ϫ T cells confers suppressive properties (5-7), confirming that Foxp3 in these cells is sufficient to suppress proliferation and cytokine secretion by effector Th cells. Although Foxp3 itself may not specify T reg cell lineage commitment (8,9), maintenance of the regulatory phenotype in thymically derived T reg cells requires constitutive Foxp3 expression (10). Moreover, depletion of T reg cells in adult or neonatal mice induces the Scurfy phenotype, whereas adoptive transfer of relative...

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