Pg has distinct immunomodulatory properties involved in poorly understood immune phenomena, including maternal tolerance of the fetus, increased risk of certain infections during pregnancy or after Pg birth control, and pregnancy-associated remission of autoimmune disease. Several potential mechanisms have been identified, including alteration of Th1 and Treg activity, but the precise cellular and molecular targets of Pg immunomodulation in vivo remain obscure, partly because Pg can signal through several different receptor types. One such receptor, the iPR, encoded by the pgr gene, is essential for reproduction in female mice and is expressed in the thymus and CD4(+) T cells. We hypothesized that iPR regulates CD4(+) T cell activity and adaptive immune responses in vivo. With the use of iPR KO mice, we demonstrate that iPR specifically suppresses TD antibody responses, primarily by dampening CD4(+) Teff activity, likely via transcriptional repression of the IFN-γ gene and modulation of other programs regulating CD4(+) T cells. Our results highlight a novel mechanism linking the endocrine and immune systems, and they offer insight into important but poorly understood phenomena in women's health and autoimmunity.