Breaking Free of Control: How Conventional T Cells Overcome Regulatory T Cell Suppression

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.

Treatment of Children with Persistent and Chronic Idiopathic Thrombocytopenic Purpura: 4 Infusions of Rituximab and Three 4-Day Cycles of Dexamethasone

“…This mirrors the phenomena of difficult to cure, long-standing disease that has been described in many different autoimmune diseases of childhood and “autoimmune expansion” may be but one of the underlying mechanisms. 31 To the extent that our “T cell hypothesis” is correct, this would suggest that the failure of 4R+3Dex in these instances may be secondary to lack of anti-T cell agents in this particular combination. The addition of an agent such as mycophenolate mofetil to the 4R+3Dex regimen may contribute to curative therapy in a higher number and broader spectrum of patients.…”

Phosphatase inhibitor PPP1R11 modulates resistance of human T cells toward Treg-mediated suppression of cytokine expression

“…Furthermore, since the MAPK, AKT, and NF‐κB pathways crosstalk via several molecules, it is possible that PPP1R11 affects joint signaling molecules between the two pathways. Besides, there have been extensive clinical and experimental reports indicating that the MAPK and AKT signaling pathways are involved in inducing T cell resistance to Tregs . In light of these findings, we speculate that targeting these pathways by modulating PPP1R11 may be exploited as a novel therapeutic option for autoimmune diseases in the future.…”

“…We and others have shown that Treg‐mediated rapid suppression of T cells is mediated via modulation of NFAT, AP‐1, and/or NF‐κB pathways with differences depending on the particular cell types, stimulation, and readouts used . Furthermore, clinical and experimental studies have reported the involvement of PI3K and protein kinase B (AKT; that are downstream of CD28 signaling) to be involved in inducing resistance in T cells . Given these studies, Tregs seem to affect multiple signaling pathways in target T cells in a context‐dependent manner.…”

“…Several therapeutic approaches to target Tregs in autoimmune diseases and cancers have shown remarkable progress in recent years. However, it is alarming to realize that in several autoimmune diseases, there have been multiple reported cases of resistance of T cell toward Treg‐mediated suppression . We have recently performed the first global analysis to systematically study signaling molecules affected by Treg‐mediated suppression in conventional T cells (Tcons) by phosphoproteomics .…”

“…However, it is alarming to realize that in several autoimmune diseases, there have been multiple reported cases of resistance of T cell toward Treg-mediated suppression. 3,8,9 We have recently performed the first global analysis to systematically study signaling molecules affected by Treg-mediated suppression in conventional T cells (Tcons) by phosphoproteomics. 10 and survival such as activatory cytokines and other immunostimulatory molecules.…”