Nuclear receptor LRH-1 regulates early T cell development in mice

T cell development in the thymus requires tightly coordinated transcriptional programs that regulate lineage commitment, proliferation and differentiation. While key transcription factors controlling these processes have been extensively characterized, the contribution of the low expressed nuclear receptor Liver Receptor Homolog 1 (LRH-1, Nr5a2 ) in T cell development remains unexplored. Here, we investigated the role of LRH-1 in thymocyte maturation using an inducible ex vivo deletion system and in vivo Lck-Cre- and CD4-Cre-mediated LRH-1 knockout mouse models. We demonstrate that inducible LRH-1 deletion impairs early thymocyte development, identifying LRH-1 as a critical regulator of the double negative (DN)2/DN3 to DN4 transition. Early Lck-Cre-mediated deletion of LRH-1, but not CD4-Cre-mediated deletion at the double positive stage, resulted in markedly reduced thymic size and cellularity, indicating a stage-specific requirement for LRH-1 during thymopoiesis. Lck-Cre-mediated LRH-1 deletion led to a decreased frequency of mature CD4⁺ T cells in peripheral lymphoid organs, while the remaining mature T cells were predominantly Cre reporter-negative and therefore escaped LRH-1 deletion. CD4⁺ T cells that escaped Cre-mediated LRH-1 deletion exhibited impaired T cell activation marker expression and cytokine secretion. In vivo , these defects resulted in attenuated T cell effector function and compromised regulatory T cell-mediated protection in a T cell transfer model of colitis, indicating impaired effector and regulatory T cell function under (patho)physiological conditions.

Collectively, our findings identify LRH-1 as a critical, previously unrecognized regulator of early thymocyte development, and establish its essential role in shaping functional peripheral CD4⁺ T cell-mediated immune responses.