Maternal Regulatory T Cells: One of Mother’s (and Baby’s) First Lines of Defense

Maternal regulatory T cells play a vital role in maintaining maternal-fetal tolerance and sustaining pregnancies.  By better understanding the mechanisms by which maternal regulatory T cells mediate immune reactions during pregnancy and how pathogens manipulate such immune reactions, it is possible to develop preventative measures against opportunistic pathogens that target mothers during this critical period of time.

In many ways, the immune system’s response to pregnancy is akin to that of organ transplantation; the maternal immune system must determine if the growing fetus poses a threat to the mother’s own survival and if it must be rejected (Gobert and Lafaille 2012). This problem results from the fetus being semiallogenic in nature, meaning that it expresses a combination of both maternal and paternal antigens (Gobert and Lafaille 2012). However, despite the fact that the paternal antigens are considered foreign by the maternal immune system, most maternal immune systems do not cause significant damage to the developing fetus.  This is made possible by the establishment of maternal-fetal tolerance, which increases the probability that the mother’s body will instead perceive the baby as “temporary self” (Trowsdale and Betz 2006).  However, establishing a maternal-fetal tolerance puts the mother at risk by limiting the capacity of her immune system to identify other foreign pathogens that could cause her harm.  Therefore, many non-overlapping mechanisms have evolved to maintain a delicate balance between immunosuppression – to protect the fetus from the maternal immune systems – and immune reactivity – to protect both mother and child from invading pathogens (Munoz-Suano, Hamilton and Betz 2011).   Recent research into maternal-fetal tolerance seeks to shed some light on these mechanisms, particularly those mediated by a subpopulation of T cells called regulatory T cells (T_regs) (Gobert and Lafaille 2012, Munoz-Suano, Hamilton and Betz 2011, Rowe, et al. 2013).

Immunosupression in HIV/AIDS Mediated by Myeloid Derived Supressor Cells

MDSCs: Gabrilovich & Nagaraj, Nat Rev Immunol 2009

Recently, researchers have found a new subset of immune cells that functions to suppress immunity in multiple diseases. Early research has identified them as myeloid-derived suppressor cells (MDSCs), a heterogenous group of immature myeloid cells, divided into granulocytic or monocytic subsets (CD15 or CD14). Recent research has focused on their role in tumor immunology; Hosoi et al showed that during adoptive CTL (cytotoxic T lymphocyte) treatment of cancer (melanoma), CTLs triggered expansion of MDSCs that eventually outnumbered CTLs, secreted reactive oxygen and nitrogen species, and prevented further proliferation of CTLs. This research in cancer biology shows that immunotherapy and immune response can trigger a counter-regulatory response that dampens the immune system. In a recent paper, Ankita Garg and Stephen Spector tested the roles of MDSCs in viral infection, specifically HIV/AIDS, and found a very similar suppressive effect. As not much is known about the mechanisms behind how MDSCs function in the immune response, these authors used HIV infection of PBMCs and co-culture techniques to explore how MDSCs suppress immunity, covering their expansion, function, and mechanisms of function.

Origin of MDSCs; Gabrilovich & Nagaraj, Nat Rev Immunol 2009

To start, the authors treated PBMCs (peripheral blood mononuclear cells) with heat-inactivated or infectious HIV, or gp120, a HIV envelope glycoprotein responsible for binding to the CD4 co-receptor on a helper T cell and allowing the HIV envelope glycoprotein gp41 to contact the host cell membrane and promote viral fusion (see HIV and Neurocognitive Dysfunction). Both infectious HIV and inactivated HIV/gp120 were able to induce expansion of MDSCs (in this paper gated as CD11b⁺CD33⁺CD14⁺HLA-DR^-/lo; see note), suggesting that viral replication is not necessary of induction of MDSCs. Next, they looked that how gp120 was able to induced MDSC expansion, and found that PBMCs cultured with gp120 conditioned media showed increased an MDSC population, and found increased levels of IL-6, a major inflammatory cytokine, in gp120-treated PBMC supernatants, leading them to hypothesize that IL-6 was responsible for inducing MDSCs. They confirmed this by showing IL-6 neutralization inhibited MDSC expansion. Furthermore, they surmised that IL-6 would be acting through its STAT3 pathway (a major pathway for IL-6 signaling), and found increased levels of phosphorylated STAT3 (pSTAT3) in gp120-treated PBMCs. They showed that IL-6 neutralization completely abolished pSTAT3 expression in gp120-treated PBMCs, showing that IL-6 may cause MDSC expansion via signaling through the STAT3 pathway.

Stopping Autoimmunity at its Roots: New Advances in the Treatment of Lupus Nephritis

Autoimmune diseases are the result of our own immune systems turning against us. There are various mechanisms through which autoimmunity can develop, most of which involve the breakdown in peripheral tolerance, which are the mechanisms our body puts in place to keep autotreactive T and B cells from damaging self tissue. If an autoreactive lymphocyte escapes central tolerance and finds its way to the periphery, it becomes the job of regulatory T cells (Treg cells) or tolerogenic DCs to anergize or delete the autoreactive lymphocyte. If there are abnormalities in regulatory T cells, then peripheral tolerance is hindered and an autoimmune disease could develop. Other conditions could result if problems exist in compliment deposition since C3b is responsible for helping immune complexes remain soluble when they pass through narrow channels in the body’s periphery. When cells are destroyed during an autoimmune attack, internal cell contents can be leaked and then work as antigens for the activation of additional lymphocytes. This occurrence may perpetuate an autoimmune response. Regardless of the mechanism, these responses are damaging to the host and require the development of effective treatments.

One damaging autoimmune disease, systemic lupus erythematosus (SLE), is caused by the production of “antinuclear” antibodies which target internal cell components such as DNA when these molecules are released from cells. This disease can affect the skin, joints, kidney, lung, heart, and brain. Since SLE’s symptoms are often varied, the disease can be mistaken for other illnesses. The mechanism of action of SLE has been linked to abnormal B cell development and activation. These B cells are also more sensitive to cytokines than would normally be expected. Furthermore, the fact that an increase in IL-10, a B-cell stimulating molecule, has been associated with SLE patients provides additional evidence that this disease is caused by B cells. This observation is interesting because typically we associate IL-10 as an immunosuppressive cytokine, however in the case of SLE patients, the immunostimulatory effects of IL-10 on B cells appear to outweigh its immunosuppressive value (1). SLE is considered to be a type-III hypersensitivity because these activated B cells produce autoantibodies that can form insoluble immune complexes that basically “clog up” narrow capillaries or other parts of the body such as the glomerulus, a spherical structure in the kidneys which filters blood. As a result, many SLE patients manifest the serious disorder called lupus nephritis. Lupus nephritis is a major cause of morbidity and mortality among SLE patients (2). It results when immune complexes interfere or cause damage to structures in the kidney, such as the glomerulus, and can rapidly worsen to kidney failure. Treatment for lupus nephritis typically focuses on the use of medications to suppress the immune system in order to improve kidney function. Dialysis, to control symptoms of kidney failure, and kidney transplantation are other treatments that may be recommended.

Recent research by K. Ichinose and several colleagues at Beth Israel Deaconess Medical Center and Harvard Medical School has been focusing on the cause of lupus nephritis rather than on new treatments for the malady. The researchers are hoping that their efforts will lead to the development of a more targeted drug which can do more for patients than the current drugs that work by suppressing the immune system on a large scale. They chose to study mesangial cells (MC’s) in the glomerulus because they proliferate during lupus nephritis, a phenomenon that could link MC’s to the cause of this autoimmune disease. Typically, the function of these specialized cells is related to support, filtration, and phagocytosis of immunoglobulin. These cells can also produce the proinflammatory cytokine IL (interleukin)-6, found during glomerular inflammation. The researchers also looked at calcium/calmodulin-dependent kinase type IV (CaMKIV). This kinase belongs to a family of kinases that regulates autoimmunity and cell proliferation. CaMKIV is a multifunctional protein that is highly expressed in the central nervous system. Because increased expression of CaMKIV has been linked to certain cancers, some researchers see this as evidence that it is involved in cell proliferation (3). This observation led them to perform tests to ascertain whether CaMKIV could be deleted or its actions blocked, possibly leading to decreased MC proliferation and IL-6 production that could in theory alleviate an autoimmune response.

Regulatory T Cell involvement with Maternal Fetal Tolerence

Pregnancy is an emotional time for mothers. The constant mood swings, cravings, and nesting syndrome makes the 9 months seem like a lifetime. While the mother is busy attending doctor’s appointments, setting up a nursery and attempting to be ready for a child, her body’s immune system is attempting to reconcile with the fetus growing inside the womb. The immune system sees this new life as a foreign invader attempting to overwhelm the body’s systems (which it kind of is). This is a sign that the immune system should attack and rid the body of the invader. However, if the immune system did this every time a woman got pregnant; our lineage would have ended with Eve. So we as humans have evolved ways to regulate the immune system during pregnancy in order to give birth to health babies. Different stages in pregnancy bring changes in cytokine production (the immune system’s messenger, of which there are many different kinds) to modulate the inflammatory response as needed (1). These changes in cytokine production then produce changes in the cells of the immune system, macrophages (collect debris), natural killer cells (does just what it sounds like it does, kills foreign cells), and regulatory T cells (regulates the other cells in the immune system) (2). Even though these regulatory actions exist there still exists evidence that the maternal immune system can and does respond to fetal antigen (fetal cells).

The presence of maternal antibody (the immune system’s detector) to major histocompatibility complex (MHC) (the complex that presents foreign material) suggests that CD4 T cells can participate in anti-fetal responses (2). A study on the modification of immune cells during pregnancy done by Elizabeth Bonney, examined spleen CD4 T cells of both normal mice and a unique CD4 T cell receptor transgenic mouse specific for the male antigen H-Y (a genetically mutated mouse that cause rejection of fetal material when mated with another H-Y mouse)(3). They found that during pregnancy, these transgenic CD4 T cells become activated and multiply in response to specific antigen and modulate the expression of the CD4 co-receptor (receptor that helps CD4 bind). This data suggest that during pregnancy this particular T cell pool is dynamic and further suggests that there is a specific mechanism of regulation that helps to maintain the coexistence between fetal tolerance and maternal T cell responsiveness.

Regulatory T Cells in Patients with Whipple's Disease

Classical Whipple’s Disease (CWD) is a rare, multisystemic infection of the duodenal mucosa. Macrophages infected with Tropheryma whipplei, a gram positive bacterium, first attack the intestinal mucosa and then disperse throughout the body to the intestinal epithelium, capillary and lymphatic endothelium, synovium, heart, lungs, liver, brains, eyes and skin. Symptomatic manifestations are most commonly reported in the intestines, and include weight loss, diarrhea, and abdominal pain (Schijf et.al 394). Additionally, T.whipplei infection can spread to the brain and heart and cause inflammation of the heart muscle. [1]

Schinnerling and colleagues argue that host immune deficiency plays a major role in the persistence and systematic spread of CWD. The authors suggest that healthy adults generally display an efficient humoral, or antibody, and cellular immunological response that effectively combats T.whipplei. However, immunological defects are believed to weaken the immune response and enable the pathogen to successfully infect the host [2]. The defects present in the peripheral blood and the duodenal mucosa of CWD patient include, but are not limited to, impairment of T cell proliferation, and diminished Th1 reactivity.

T cells are a type of white blood cell that helps recognize and eradicate invading pathogens that cause disease. Th1 cells are a brand of T cells that specialize in intracellular pathogen disposal. Specifically, Th1 cells secrete IL-2, IFN­-y, and LT, which are cytokines, or signaling chemicals, that initiate a robust inflammatory response. A Th1 response is generally avoided in mucosal tissues because inflammation is an aggressive immune response that can damage the delicate tissue of the mucosa. Consequently, a Th2 response is initiated in the mucosa to avoid cell damage and effectively combat extracellular pathogens. Th2 cells secrete cytokines, such as IL-4, IL-5, and IL-10, to suppress a Th1 response and initiate antibody production. Antibodies neutralize pathogens without damaging surrounding host cells [3].

Tissue Associated Tregs May Explain Why Some Children Have Persistent Ear Infections

Maybe you know a small child who just can’t seem to shake an ear infection. Maybe, at one time, you were that child. There is good news; immunologists may be one step closer to understanding why the infection is sticking around.

Streptococcus pneumoniae (pneumococcus) is a harmful bacterium that causes millions of deaths every year. Pneumonia, meningitis, and ear infections (otitis media) are all the handiwork of this bacterium. Young children often carry pneumococcus until age three. By that time, their adaptive immune response (not the primary line of defense but the very specific, memory based line of defense) either prevents the infection or quickly removes it with the help of the immune cells in the NALT (nasal-associated lymphoid tissue).

It is curious, then, how some children who display immunological memory for the pathogen continue to carry the infection in their nasopharynx. A recent study Zhang et. al. in PLoS Pathogens suggests that regulatory T cells (Tregs) may be responsible for allowing the infection to persist.