The Role of Paternal T cells in Epigenetic Inheritance of Sebum Secretion

Parental experiences such as diet and stress can affect the phenotype of subsequent generations through non-genetic inheritance. This process, where phenotypic changes are passed on without altering the DNA sequence, can alter phenotypes of the F1 generation of mice or even beyond. While epigenetic inheritance to the F1 generation is well-established in mammals, beyond the F1 generation to the F2 generation and further has only been demonstrated in organisms, like C. elegans and plants. The mechanisms behind epigenetic inheritance beyond the F1 generation in mammals are still poorly understood due to a lack of robust and easily quantifiable phenotypes. Our labs have recently uncovered that T cells can epigenetically alter phenotypes across generations. T cell-deficient male mice and their F1 and F2 offspring generated by crossing to WT mice exhibited defective sebum secretion. Mice lacking CD4-/CD8- double negative (DN) T cells were also found to have defective sebum secretion. These discoveries provided a novel model to study how T cells, including DN T cells, can epigenetically alter progeny phenotype. It is hypothesized that the epididymis, a long, convoluted tubule in the male reproductive tract, secretes extracellular vesicles filled with small regulatory RNA (sRNA) to alter sperm sRNA expression that can transfer epigenetic information to the next generation zygote. We have observed that T cell- deficient mice had dysregulated small regulatory RNA (sRNA) and gene expression in both sperm and the epididymis, suggesting that T cells may interact with the epididymis to alter these processes. We hypothesize that T cell activity (specifically DN T cells) alters the gene and sRNA expression of the epididymis and sperm, resulting in the transfer of sebum secretion phenotypes to succeeding generations of progeny. Our research aims to address the following. (Aim 1) We will characterize the expression landscape and function of epididymal DN T (eDNT) cells by analyzing (1) immmunophenotype through flow cytometry and transcriptional profile through single cell RNAseq, as well as (2) DN T cell-derived immunoregulatory cytokines effects on epididymis gene and sRNA expression. (Aim2) Second, we will determine how eDNT cells affect the (1) sperm sRNA expression and epididymis gene and sRNA expression, (2) the inheritance pattern of epigenetically heritable defective sebum secretion, and (3) epigenetic inheritance of sebum secretion. This work aims to probe potential mechanisms that drive epigenetic inheritance, linking the parental immune state to phenotypic alterations in future generations through the activities of eDNT cells. To work towards my career goal to become a principal investigator, I have outlined a training plan at the University of Pennsylvania, focusing on experimental design, scientific communication, research collaboration, and mentorship skills. The resources at Penn offer an ideal environment for my growth as an immunologist and epigeneticist, providing the opportunity to integrate research in immunology and epigenetics. Project Number: 1F31HD121392-01 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Simon Zhou | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $50,114 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F10B-Q (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31HD12139201