Abstract
Split immunological tolerance refers to states in which an individual is capable of mounting certain types of immune responses to a particular antigenic challenge, but is tolerant of the same antigen in other compartments of the immune system. This concept is applicable to the immunological relationship between mother and fetus, and particularly relevant in equine pregnancy. In pregnant mares, antibody responses to paternal foreign Major Histocompatibility Complex class I antigens are robust, while anti-paternal cytotoxic T cell responses are diminished compared to those mounted by non-pregnant mares. Here, we compared the distribution of the major lymphocyte subsets, the percentage of lymphocytes expressing Interferon Gamma (IFNG) and Interleukin 4 (IL4) and the level of expression of the immunoregulatory transcription factor FOXP3 between pregnant and non-pregnant mares, and between peripheral blood and the endometrium during pregnancy. In a cohort of mares in which peripheral blood lymphocytes were tested during early pregnancy and in the non-pregnant state, there were only slight changes observed during pregnancy. In contrast, comparison of peripheral blood lymphocytes with lymphocytes isolated from the endometrial cups of pregnant mares revealed striking differences in lymphocyte sub-populations. The endometrial cups contained higher numbers of IFNG+ lymphocytes, and lower numbers of lymphocytes expressing IL4. The endometrial cup lymphocytes also had higher numbers of FOXP3+ cells compared to peripheral blood lymphocytes. Taken together, these results strengthen the evidence for a state of split tolerance to trophoblast, and furthermore define sharp differences in immune reactivity during equine pregnancy between peripheral blood lymphocytes and lymphocytes at the maternal-fetal interface.
Highlights
The paradox of the successful fetus-as-allograft paradigm was first proposed by Peter Medawar in 1953, and hypotheses put forth in that classic paper have generated numerous clinical and experimental studies in the field of pregnancy immunology
56 years later, many strategies and mechanisms have been identified that may explain how the fetus escapes recognition and destruction by the maternal immune system. These include repression of expression of alloantigens and tissue specific antigens in the placenta, systemic alterations in the character of maternal immune responses during pregnancy, and locally operating mechanisms of trophoblast cells that protect the fetal tissues against destruction by maternal immune effector cells and molecules
First is the question of systemic changes in maternal immune reactivity during pregnancy, and second is the relevance of those changes in the periphery to local immunological events at the fetal-maternal interface
Summary
The paradox of the successful fetus-as-allograft paradigm was first proposed by Peter Medawar in 1953, and hypotheses put forth in that classic paper have generated numerous clinical and experimental studies in the field of pregnancy immunology. The second part of this study compared immune reactivity of equine peripheral blood lymphocytes with tissue lymphocyte populations from the endometrium in samples obtained at necropsy in a group of six pregnant mares between days 43 and 46 of gestation. Using gates set for lymphocytes, the percentages of cells expressing equine CD4, CD8, and the B-cell marker CD19 were determined and compared to values obtained from peripheral blood samples taken from the mares on the day of necropsy. PCR assays were used to compare the expression of FOXP3 protein and messenger RNA in paired samples of CD4+ lymphocytes from the endometrial cups and peripheral blood of pregnant mares (Fig. 8). It is likely that these CD4+, FOXP3+ lymphocytes represent equine regulatory T cells
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