Th1/Th2 Helper T Cells and Pregnancy: Research Review

Some immune cells, like T helper cells, produce molecules that tell the immune system to either kick into high gear (pro-inflammatory) or calm down (anti-inflammatory). Th1 cells are T helper cells that produce pro-inflammatory molecules, while Th2 cells produce anti-inflammatory molecules. The ratio of Th1 to Th2 can help determine a patient’s inflammation levels.

Whether caused by an autoimmune condition, infection, allergies, or another source, inflammation has been associated with reproductive challenges. During a healthy pregnancy, the body must be able to shift to a relatively anti-inflammatory state to maintain the pregnancy.

Physiology

CD4+ T cells, CD8+ T cells, NKT cells, and NK cells comprise four of the major effector cell types of the immune system. These cells can respond to the presence of foreign antigens, including paternally derived antigens present on conceptuses, and elicit either immunogenic or tolerogenic responses.  

Naïve CD4+ T cells can differentiate into one of several lineages upon antigen priming by antigen presenting cells (APCs) depending on the nature of the APCs involved and the profile of soluble molecules secreted by the APCs during priming.  These lineages include Th1, Th2, Th17, and Treg cells (regulatory T cells) which are distinguished by unique cytokine expression profiles.  Cells expressing these cytokines (IFNg for Th1, IL-4 for Th2, IL-17 for Th17, and IL-10 for Treg) can be identified by flow cytometry and ratios of these cells can be determined to characterize the CD4+ T cell lineage profile for an individual.  Analogous lineages also exist for CD8+ T cells, NKT cells, and NK cells which can be similarly characterized.  Levels of TNFa positive cells can also be used as a general marker of cellular activation. 

Relative balances of these lineages within each of these cell types can be used to help characterize the nature of any underlying immune conditions.  For example, some autoimmune conditions such as rheumatoid arthritis are Th1-dominant, whereas other autoimmune conditions such as systemic lupus erythematosus are Th2-dominant.  Other conditions including endometriosis, PCOS, and atopy are also characterized by differential intracellular cytokine profiles.  These profiles can be present many years prior to the full clinical manifestation and diagnosis of an underlying autoimmune/inflammatory immune condition and therefore, in combination with other genetic and cellular data, can be used to characterize preclinical/asymptomatic conditions that may affect the immune response to foreign antigens.

Changes in intracellular cytokine profiles can also be used to track the maternal immune response to pregnancy, assess the efficacy of immune treatment, and determine if any failures of pregnancy are immunological in nature.  

Published clinical data

Altered intracellular cytokine profiles have been found in the peripheral blood of women with a history of recurrent implantation failure or recurrent miscarriage.  These include an elevated ratio of Th1 to Th2 cells, elevated levels of TNFa positive cells, decreased levels of IL-10 positive cells, and increased levels of Th17 cells^1-2. 

The normal (non-pathological) response to pregnancy is characterized by a tolerogenic response to paternal antigens present on the conceptus.  This tolerogenic response is characterized by specific changes to the intracellular cytokine profile of various immune cell types.  These tolerogenic responses include a shift to Th2 dominance (a decrease in the Th1/Th2 ratio) and an increase in levels of IL-10 positive cells^3-4.

Pathological immune responses to a conceptus involve a failure to properly develop immunological tolerance to paternally derived antigens. Rather, an immunogenic response is elicited which can lead to cellular and/or humoral (antibody-mediated) responses.  Such pathological immune responses to a conceptus can result in various clinical manifestations including implantation failure, spontaneous abortion, preeclampsia, intrauterine growth restriction (IUGR), and stillbirth. 

Defective development of immunological tolerance during pregnancy is characterized in the peripheral blood in part by a failure in a shift to Th2 dominance, a failure in the increase in IL-10 positive cells and increases in levels of IL-17 positive cells^5-6.

About Pregmune: We’re an innovative reproductive health technology company, built on a solid foundation of data gained from decades of experience and thousands of successful pregnancies. Our team of fertility specialists and scientists are using artificial intelligence to decipher the complexity of the immune system and help patients grow the families of their dreams.

Our first product, IRMA, provides patients and their doctors with a personalized report and evidence-based treatment plan that addresses immunological sources of unexplained infertility, recurrent pregnancy loss, and recurrent implantation failure.

References

1. Yockey LJ, Iwasaki A. Interferons and Proinflammatory Cytokines in Pregnancy and Fetal Development. Immunity. 2018 Sep 18;49(3):397-412. doi: 10.1016/j.immuni.2018.07.017. PMID: 30231982; PMCID: PMC6152841.
2. Raghupathy R, Kalinka J. Cytokine imbalance in pregnancy complications and its modulation. Front Biosci. 2008 Jan 1;13:985-94. doi: 10.2741/2737. PMID: 17981605.
3. Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am J Reprod Immunol. 2010 Jun;63(6):601-10. doi: 10.1111/j.1600-0897.2010.00852.x. Epub 2010 Apr 23. PMID: 20455873.
4. Ali S, Majid S, Niamat Ali M, Taing S. Evaluation of T cell cytokines and their role in recurrent miscarriage. Int Immunopharmacol. 2020 Mar 3;82:106347. doi: 10.1016/j.intimp.2020.106347. Epub ahead of print. PMID: 32143004.
5. Sykes L, MacIntyre DA, Yap XJ, Teoh TG, Bennett PR. The Th1:th2 dichotomy of pregnancy and preterm labour. Mediators Inflamm. 2012;2012:967629. doi: 10.1155/2012/967629. Epub 2012 Jun 7. PMID: 22719180; PMCID: PMC3376783.
6. Raghupathy R. Pregnancy: success and failure within the Th1/Th2/Th3 paradigm. Semin Immunol. 2001 Aug;13(4):219-27. doi: 10.1006/smim.2001.0316. PMID: 11437629.