The role of t cells in transgenerational epigentic inheritance

The National Institute of Child Health and Human Development awarded The Trustees of the University of Pennsylvania $704,336 on August 17, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to investigate the role of T cells in transgenerational epigenetic inheritance.

The funded research examines how the immune system, specifically T cells, can epigenetically alter phenotypes across multiple generations of progeny. Preliminary data demonstrates that T cell-deficient mice display defects in sebum secretion, a lipid-rich substance providing skin barrier function. When T cell-deficient male mice are bred with wildtype females, resulting F1 and many F2 progeny exhibit sebum secretion defects despite possessing normal T cell numbers. The research also identifies striking alterations in gene expression of embryos produced by fertilizing wildtype eggs with sperm from T cell-deficient mice. The proposed mechanism involves altered small regulatory RNA profiles in mature sperm from T cell-deficient mice, particularly small RNAs transferred by extracellular vesicles called epididymosomes from epididymal epithelial cells to sperm during epididymal transit. The work encompasses investigation of gene expression and small RNA profiles in the epididymis of T cell-deficient versus wildtype mice.

The project period extends from August 17, 2026, through May 31, 2031. Work is performed in Philadelphia, Pennsylvania.

Abstract

The environment (e.g., toxins, diet) and experiences (e.g., stress) of parents can non-genetically influence the phenotypes of succeeding generations of progeny. In humans, these epigenetically inherited phenotypes include increased susceptibility to cardiovascular and metabolic diseases, which are transmitted not only by the mother but also by the father. While intergenerational non-genetic inheritance from the parents directly to F1 progeny has been widely documented in rodent models, multigenerational epigenetic inheritance to succeeding generations of progeny (F2 and beyond) has remained controversial in mammals. In this proposal, we provide preliminary data demonstrating that the immune system, specifically t cells, can epigenetically alter phenotypes of progeny across multiple generations. We find that t cell-deficient mice display a robust defect in secretion of sebum, a lipid-rich substance that provides skin barrier function. Surprisingly, breeding t cell-deficient male mice to wildtype (WT) females also yields progeny with a sebum secretion defect in the F1 and in many of the F2 progeny, despite normal number of t cells in these mice. Moreover, we find striking alterations in gene expression of embryos produced by fertilizing WT eggs with sperm from t cell-deficient mice compared to WT sperm fertilized embryos. As a potential mechanism to transfer epigenetic information to the embryo, we found that the small regulatory RNA profile of mature sperm from t cell-deficient mice was markedly different from WT mice, especially the small rnas that are transferred by extracellular vesicles, called epididymosomes, from epididymal epithelial cells to sperm as they travel through the epididymis. Indeed, we find that gene expression and the small RNA profile of the epididymis is altered in t cell-deficient compared to WT mice. Moreover, the inverse correlation between small rnas in the epididymis and mature sperm suggests that epididymal RNA packaging and epididymosome release drive t cell-dependent changes in sperm small rnas. Based on these preliminary data, we hypothesize that t cells alter epididymal packaging of RNA into epididymosomes, which modifies small rnas in sperm to regulate early embryonic gene expression and phenotypes of progeny across multiple generations. We will test this hypothesis in two separate aims. In aim 1, we will determine how t cells affect the epididymis and small rnas in sperm. Experiments in aim 2 will determine how sperm small rnas regulated by t cells modulate embryonic development and epigenetic inheritance. This proposal is the result of an unparalleled and productive collaboration between an expert in epigenetic inheritance (DR. Conine) and immunology (DR. Kambayashi). This work will uncover how t cells control epigenetic inheritance, providing foundational mechanistic evidence for its multigenerational transmission in mammals. By defining how the immune system shapes epigenetic inheritance, this work will transform our understanding of inheritance across generations