Differential effects of estradiol and progesterone on human T cell activation <i>in vitro</i>

Estradiol (E2) and progesterone (P4) are steroid hormones important for the regulation of immune responses during pregnancy. Their increasing levels coincide with an improvement of T cell‐mediated diseases such as multiple sclerosis (MS). Although immune‐endocrine interactions are involved in this phenomenon, the relative contribution of hormones is not known. We here report a direct comparison of E2‐ and P4‐mediated effects on human CD4⁺ T cells, key cells in immune regulation. T cells were stimulated to obtain different activation levels and exposed to a broad range of hormone concentrations. Activation level was assessed by CD69/CD25 expression by flow cytometry, and secreted proteins (n = 196) were measured in culture supernatants using proximity extension assay and electrochemiluminescence immunoassay. We found that in low activated cells, pregnancy‐relevant E2 concentrations increased activation and the secretion of several immune‐ and inflammation‐related proteins. P4, on the other hand, showed a biphasic pattern, where serum‐related concentrations upregulated activation and protein secretion while placenta‐relevant concentrations induced a prominent dampening irrespective of the initial activation level. Our results demonstrate the importance of P4 as a major hormone in the immune modulation of T cells during pregnancy and emphasize the need to further evaluate its potency in the treatment of diseases like MS.