The T helper type 17/regulatory T cell paradigm in pregnancy

Abstract

T helper type 17 (Th17) and regulatory T (Treg) cells are active players in the establishment of tolerance and defence. These attributes of the immune system enmesh to guarantee the right level of protection. The healthy immune system, on the one hand, recognizes and eliminates dangerous non-self pathogens and, on the other hand, protects the healthy self. However, there are circumstances where this fine balance is disrupted. In fact, in situations such as in pregnancy, the foreign fetal antigens challenge the maternal immune system and Treg cells will dominate Th17 cells to guarantee fetal survival. In other situations such as autoimmunity, where the Th17 responses are often overwhelming, the immune system shifts towards an inflammatory profile and attacks the healthy tissue from the self. Interestingly, autoimmune patients have meliorating symptoms during pregnancy. This connects with the antagonist role of Th17 and Treg cells, and their specific profiles during these two immune challenging situations. In this review, we put into perspective the Th17/Treg ratio during pregnancy and autoimmunity, as well as in pregnant women with autoimmune conditions. We further review existing systems biology approaches that study specific mechanisms of these immune cells using mathematical modelling and we point out possible future directions of investigation. Understanding what maintains or disrupts the balance between these two opponent yet reciprocal cells in healthy physiological settings, sheds light into the development of innovative pharmacological approaches to fight pregnancy loss and autoimmunity.

Keywords: T helper type 17/regulatory T cell ratio; autoimmunity; defence; mathematical modelling; pregnancy; systems biology; tolerance.

Figure 1

Illustrative scheme of naive T cell differentiation into T helper type 1 (Th1), Th2, Th17 or regulatory T (Treg) cells, depending on the cytokine profile. Interleukin‐12 (IL‐12) and interferon‐γ (IFN‐γ) stimulated naive T cells differentiate to Th1 cells. These cells express IFN‐γ and tumour necrosis factor‐α (TNF‐α), and are responsible for intracellular parasite clearance and allergy conditions. IL‐4 stimulated naive T cells induce a Th2 response. Th2 cells express IL‐4, IL‐5, IL‐6 and IL‐13, and are responsible for clearance of extracellular parasites. Transforming growth factor‐β (TGF‐β) stimulated naive T cells induce a Treg response. Treg cells express TGF‐β and IL‐10 and are responsible for tolerance and pregnancy success. These three cell types express one cytokine responsible for its induction, in a positive feedback mechanism. TGF‐β and IL‐6 stimulated naive T cells induce a Th17 response. Th17 cells express IL‐17, IL‐21 and IL‐22 and are responsible for autoimmunity and pregnancy loss. Th17 cells do not present a positive feedback mechanism, but IFN‐γ or IL‐4 can inhibit the differentiation from naive T cells to Th17. Moreover, IL‐6 and IL‐12 inhibit Treg and Th2 cells, respectively.

Figure 2

Illustrative description of the T helper type 17 (Th17)/regulatory T (Treg) balance in (a) pregnancy complications and autoimmunity and (b) a healthy pregnancy and self tolerance. Abbreviations: MS, multiple sclerosis, PE, pre‐eclampsia, PTB, preterm birth; RA, rheumatoid arthritis; SLE, systemic lupus erythemsatosus; URPL, unexpected recurrent pregnancy loss.