Regulatory T Cells in Pregnancy: Will the Real Tregs Please Stand Up?

Posted By Dr. Braverman || 26-Mar-2013

A critical role for regulatory T cells (Tregs) in establishing and maintaining tolerance of the maternal immune system toward an embryo / fetus has been known now for several years. Tregs are a specialized subset of T cells that function through several mechanisms, including secretion of soluble factors such as IL-10, to suppress the maternal immune response to "foreign" paternal components (antigens) expressed by the embryo. This includes suppression of both cellular immune responses mediated by effector T cells (Teffs) and humoral (antibody) responses mediated by B cells that would otherwise target and attack embryonic cells expressing paternal antigens.

More recently it has been discovered that Tregs are themselves further composed of several subpopulations with specialized functions. Two major subsets of Tregs are termed natural Tregs (nTregs) and adaptive or inducible Tregs (iTregs). nTregs are generated in the thymus and generally function to suppress immune responses to "self" antigens (antigens produced from your own normal proteins in your cells) while iTregs are generated outside of the thymus in various tissues and generally function to suppress immune responses to "foreign" antigens (antigens produced from proteins in cells foreign to your body). Several months ago on this blog we reported on a landmark study from researchers at Memorial Sloan Kettering Cancer Center in NYC which elegantly demonstrated that it is iTregs and not nTregs that are critical to establish immune tolerance to the embryo and prevent miscarriage in mammals.

At Braverman IVF & Reproductive Immunology we believe that measuring Treg levels is an important component to diagnostic analysis of our patient's immune systems and monitoring of its response to pregnancy. We have been performing these tests for several years, giving us extensive experience and expertise in this area. Detecting the levels of any cell type in a sample from a patient requires the ability to specifically identify that cell type according to its expression of unique combinations of "markers." For Tregs, the markers that are most frequently used are CD4, CD25 and FoxP3. CD4 and CD25 broadly identify T cells and FoxP3 further identifies the subset of the T cells that are Tregs. While the combination of these markers is fairly specific for Tregs it has been shown that FoxP3 can also be transiently expressed in activated effector T cells. Therefore, we have recently incorporated the use of an additional marker, CD127, to more specifically identify Tregs (it is actually the absence of CD127 that further identifies Tregs, so we select "against" this marker).

While our current test for Tregs using CD4, CD25, FoxP3 and CD127 as markers is highly specific for Tregs, and to our knowledge more advanced than any other test for Tregs currently in clinical use, we believe that the diagnostic utility of Treg cell measurements can be further enhanced by even more specific identification of the Treg subpopulations most relevant to pregnancy. To this end, we are now working on incorporating additional markers to specifically identify the iTreg subpopulation that is critical to pregnancy.

It is now also becoming clear from recent literature that the activity of Tregs can be modified by their local environment, including by the presence of some cytokines. A very recent study published in the prestigious journal Nature Medicine in particular demonstrated that the cytokine TNF-alpha can suppress Treg function by causing an alteration to FoxP3 (removal of a phosphate group). This alteration reduces the activity of FoxP3 and subsequently the suppressive function of Tregs. In light of these studies we are now also actively pursuing new tests to assess the phosphorylation status of FoxP3 in Tregs and also directly assess the suppressive function of Tregs using in vitro tests.

At Braverman IVF & Reproductive Immunology we are constantly striving to identify and incorporate the latest advances in reproductive immunology research into our clinical practice in order to provide our patients access to the most cutting-edge diagnostics and therapeutics possible. These new tests to identify iTregs in patient samples and assess their functional capacity through FoxP3 phosphorylation and in vitro tests will greatly enhance our ability to test for defects in this critical population of immune regulating cells before and during pregnancy. You can contact us today to learn more.

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