Abstract
Conventional T (Tcon) cells are crucial in shaping the immune response, whether it is protection against a pathogen, a cytotoxic attack on tumor cells, or an unwanted response to self-antigens in the context of autoimmunity. In each of these immune settings, regulatory T cells (Tregs) can potentially exert control over the Tcon cell response, resulting in either suppression or activation of the Tcon cells. Under physiological conditions, Tcon cells are able to transiently overcome Treg-imposed restraints to mount a protective response against an infectious threat, achieving clonal expansion, differentiation, and effector function. However, evidence has accumulated in recent years to suggest that Tcon cell resistance to Treg-mediated suppression centrally contributes to the pathogenesis of autoimmune disease. Tipping the balance too far in the other direction, cancerous tumors utilize Tregs to establish an overly suppressive microenvironment, preventing antitumor Tcon cell responses. Given the wide-ranging clinical importance of the Tcon/Treg interaction, this review aims to provide a better understanding of what determines whether a Tcon cell is susceptible to Treg-mediated suppression and how perturbations to this finely tuned balance play a role in pathological conditions. Here, we focus in detail on the complex array of factors that confer Tcon cells with resistance to Treg suppression, which we have divided into two categories: (1) extracellular factor-mediated signaling and (2) intracellular signaling molecules. Further, we explore the therapeutic implications of manipulating the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway, which is proposed to be the convergence point of signaling pathways that mediate Tcon resistance to suppression. Finally, we address important unresolved questions on the timing and location of acquisition of resistance, and the stability of the “Treg-resistant” phenotype.
Highlights
It is well known that regulatory T cell (Treg) can employ a diverse repertoire of suppressive mechanisms, including secretion of suppressive cytokines, cytotoxicity, metabolic disruption, and modulation of antigen-presenting cell (APC) function [1]
conventional T cell (Tcon) cells can become insensitive to Treg-mediated suppression when the ratio of Tcon cells to Tregs is skewed in favor of Tcon cells, when intracellular signaling pathways have been modified by mutations, or through extracellular signals, such as strong activation or a specific cytokine milieu, that induce Tcon cell-intrinsic changes [4]
Deepening our understanding of what determines the susceptibility of a Tcon cell to Treg-mediated suppression will prove extremely useful in advancing therapies for both autoimmunity and cancer
Summary
It is well known that Tregs can employ a diverse repertoire of suppressive mechanisms, including secretion of suppressive cytokines, cytotoxicity, metabolic disruption, and modulation of antigen-presenting cell (APC) function [1]. Much work has been devoted to delineating how Treg suppressive mechanisms differ in vitro versus in vivo [2] and how these mechanisms function within specific tissues to shape immune responses [1, 3] It appeared that most mouse models of autoimmune diseases featured either qualitative or quantitative abnormalities of the Tregs, rendering them inadequate to suppress autoimmune responses [for more detail, see Ref. Tcon cells can become insensitive to Treg-mediated suppression when the ratio of Tcon cells to Tregs is skewed in favor of Tcon cells, when intracellular signaling pathways have been modified by mutations, or through extracellular signals, such as strong activation or a specific cytokine milieu, that induce Tcon cell-intrinsic changes [4] The latter mechanism refers to potentially pathogenic Tcon cells that have become resistant to Treg suppression, a phenomenon, which has been observed in several autoimmune diseases and is the focus of this review
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