The T regulatory cell is the most recent, and perhaps, the most elusive of cells of the immune system. Its discovery begins with the1908 Nobel prize in physiology and medicine jointly awarded to Ilya Mechnikov and Paul Ehrlich. They understood that the immune system must control the destructive forces that eliminate intruders. The discoveries of later Nobel prize winners, Landsteiner and Burnett, created a framework for understanding immune recognition and selection.

Were the immune system unable to distinguish self from non-self, enormous harm would be done to the tissues of the body.  In medical conditions where the immune system loses its capacity for self-recognition, a variety of diseases can occur, together known as autoimmune diseases.  These include thyroiditis, rheumatoid arthritis, some forms of diabetes, lupus as well as many others.  During the early history of modern immunology, investigators explored the mechanisms that evolved for recognition of invading organisms and cancer.  So important is this system, that the immune system developed more than a single means to limit the activity of the aggressive or cytotoxic immune response.   Prior to encountering a challenge from an invader, the immune system utilizes several mechanisms to limit the capacity of immune cells to damage the body's own tissues.  It has become clear, however, these mechanisms are imperfect.  Cells capable of attacking the self may still be found in the blood. Mechanisms now known to act locally at the very time of the immune response prevent this dreaded complication.

Dick Gershon, in the 1970s recognized this requirement for local immune restricting mechanisms.  He suggested that whenever an immune response is triggered by an inciting agent, such as an infection, two seemingly opposing responses occur. The first engages in the attack while the second turns the attack off.  In this way, the immune response is tempered, sharpening the response and limiting collateral damage. Transplant Rev. 1975;26:170-85.

Unfortunately, evidence for his regulatory theory was limited by the technology available at the time.  Gershon had no way to identify individual cells that participate in local immune responses.  Following his untimely death in 1983, his theories soon fell into disregard.  Not until 1995 when Shimon Sakaguchi identified cells using a marker present on the surface of certain immune cells (T cells) were Gershons notions rehabilitated. J Immunol. 1995 Aug 1;155(3):1151-64. A flood of research and and an enormous number of publications have since followed characterizing these cells as essential regulators of the immune response.

But Sakaguchis identification of these cells was incomplete.  Indeed, the marker he proposed was somewhat a paradox.  It was a marker that had, heretofore, been used to identify activated cells.  Activated cells are those cells that have been challenged during an immune response and divide repeatedly to form a cellular army that engages the target.   That cells expressing this activation marker would also include cells that turn down an immune response was, indeed, surprising.  Moreover, it led to ambiguity in distinguishing the two cell types.  A search for additional markers that could be used in conjunction with the original was undertaken.  The marker that seized attention was found to be a protein that interacts with DNA controlling the activation of specific genes. The protein was later identified as FoxP3. This protein was known to be defective in a generalized autoimmune syndrome found in mice as well as a counterpart in man.  It was found to have an indispensable role in the development of regulatory T cells and appeared to be a master controller for the development and function of these cells.

T regulatory cells are of central importance in pregnancy. Reprod Update. 2009 Sep-Oct;15(5):517-35. The unique immunologic challenge presented by the embryo, bearing the antigenic markings of the father, requires the induction of immune tolerance.  T regulatory cells are now understood to be central to the development of such tolerance.  Jasper and others found a reduction in the amount of the FoxP3 RNA, (the genetic counterpart of the T regulatory factor described above) in patients with unexplained infertility. Mol Hum Reprod. 2006 May;12(5):301-8.

We have corroborated these findings in studies currently being extended in our laboratory.   For example, our laboratory has observed reduced numbers of Foxp3 expressing T regulatory cells in the endometrial biopsy tissues of patients with failed implantation. Further, our laboratory has observed reduced numbers of circulating T regulatory cells in patients suffering IVF failures and early miscarriages. Our laboratory has correlated these numbers with specific clinical trends. 

Although, there is still some confusion about which cells should carry the designation T regulatory cells in the literature today, we have resolved the problem by correlating the results using the technique developed in our laboratory with the clinical findings in patients with reproductive issues.  The T regulatory cell assay, as developed by the Laboratory for Reproductive Medicine and Immunology, provides an important new diagnostic tool in the reproductive immunology repertoire.

For additional references, see:  T regulatory cell studies.