Immuno-metabolic control of the balance between Th17-polarized and regulatory T-cells during HIV infection

The discovery of retinoic acid orphan receptor (ROR)γt/RORC2 and FoxP3 as the master transcriptional regulators of Th17-polarized CD4+ effector T-cells and immunosuppressive regulatory T-cells (Tregs), respectively, changed our understanding of adaptive immunity, previously predominated by the Th1/Th2 paradigm. Th17 cells are characterized by the production of IL-17, the expression of C-C motif chemokine receptor 6 (CCR6, CD196), signal transducer and activator of transcription 3 (STAT3), and RORγt/RORC2 [1]. In addition, Th17 cells also express CCR4 (CD194) and C-type lectin CD161 [1]. These cells play a crucial role in maintaining gut mucosal immunity against pathogens and in preserving the integrity of the mucosal barrier via their cytokine secretion, mainly by IL-17A, IL-17F and IL-22 [2]. On the other hand, immunosuppressive Tregs play a pivotal role in immune tolerance and the limitation of immune activation via different immunosuppressive mechanisms and are characterized by low expression of IL-7 receptor (CD127low), high expression of IL-2 receptor (CD25high), and expression of the transcription factor FoxP3 (Fig. 1) [3], [4]. Polymorphism in RORγt/RORC2 has been linked to pathologic conditions, such as susceptibility to bacterial/fungal infections [5], while FoxP3 deficit has been linked to autoimmunity [6]. Th17 cells exhibit the capacity to dedifferentiate and become Tregs [7]. Indeed, Th17 cells and Tregs have a high level of plasticity and interconnection within their differentiation programs [8], [9]. Both share common developmental pathways regulated by their metabolism and microenvironment. Thus, the balance between pro-inflammatory signals governed by Th17 cells and anti-inflammatory signals mediated by Tregs help mediate effective and rapid immune responses against pathogens while limiting the potential of “self-damage”. Lineage flexibility is essential for immune regulation and alterations in the Th17/Treg ratios have been associated with multiple pathological conditions, including infectious diseases [10].

During SIV/HIV infection, the Th17/Treg balance is altered. Treg frequencies and activation levels are increased in peripheral blood and mucosal tissues, contributing to disease progression by inhibition of anti-viral adaptive immune responses [3], [11]. In contrast, Th17 cells are rapidly depleted due to their high permissiveness to HIV/SIV infection, resulting in increased permeability of the intestinal mucosal barrier [12], [13]. While the depletion of Th17 cells was observed in the colon of Indian rhesus macaques (RMs), in RMs of Chinese origin, in which microbial translocation is lower, it is compensated by the presence of NKT-cells expressing IL-17 in both the small and large intestines [14] indicating the importance to maintain local IL-17 production to preserve mucosal integrity. Thus, altered Th17/Treg balance in favor of Tregs contributes to generalized immune dysfunction and microbial translocation from the gut into peripheral blood (leaky gut syndrome), which causes chronic inflammation.

A growing body of evidence suggests that the metabolic status is of pivotal importance for building up an adequate immune response [15]. Immune cell proliferation and differentiation has been shown to depend on environmental factors and energetic resources such as glucose, carbohydrates, lipids and amino acids, which collectively regulate cellular metabolism and T-cell polarization [16]. Importantly, Th17 cells and Tregs utilize both distinct and complementary energetic and biosynthetic pathways necessary for their growth, proliferation, and immune function, many of which are altered during HIV infection. However, the immuno-metabolic regulation of Th17/Treg imbalance during HIV infection has not yet been well described and it is a knowledge gap that we would like to address in this review article.

留言 (0)

沒有登入
gif