Role of interleukin-6 signaling on T cell potential of aged hematopoietic stem cells and thymic progenitors

PROJECT SUMMARY/ABSTRACT T cell production declines with age and contributes to decreased immune function and increased susceptibility to infections and cancers in older adults. This decline in T cell output may be due to changes in the aged progenitor cells and/or changes in the thymic microenvironment. T cells develop from hematopoietic stem

cells (HSCs) and progenitors that enter the thymus, an organ known to atrophy with age. Previous studies looking at T cell potential from aged HSCs have been limited by the assays available; determining T cell output in vivo has relied on hematopoietic transplantation models and is confounded by the long process of engraftment and

thymic recruitment. While some in vitro models have looked at T cell output from aged HSCs and progenitors, these methods often start with a heterogenous population of cells and produce mixed conclusions about T cell potential. This proposal seeks to overcome these challenges by studying single, phenotypically-defined aged

and young HSCs and progenitors to determine T cell output and development. Further, we will determine whether a pro-inflammatory signaling pathway enhanced in aging plays a role in driving reduced thymopoiesis with age. In this proposal, Specific Aim 1 will determine the role of HSC and progenitor age on T cell development

using our in vitro Artificial Thymic Organoid (ATO) system. The ATO fully recapitulates all stages of T cell development from a single HSC or progenitor. Preliminary data from our lab suggests that aged stem cells exhibit differences at early stages of T cell development and removing aged stem cells from their inflamed

microenvironment ultimately restores their ability to produce comparable T cell numbers, emphasizing the importance of inflammatory factors in the microenvironment. Specific Aim 2 will evaluate a specific signaling pathway enhanced in aging and its effects on T cell production using a novel mouse model. Levels of the inflammatory cytokine interleukin-6 (IL-6) increase in the

aged bone marrow and thymus, and IL-6 may drive changes in the aged HSC pool (resulting in more myeloid- biased HSCs) and thymic atrophy. IL-6 requires signaling through glycoprotein 130 (gp130), and our collaborators identified a signaling modality within the gp130 receptor that produced regenerative effects in

mouse models of wound healing and osteoarthritis when inactivated. In our preliminary data, we show that these mutant mice also have greater thymocyte numbers, prompting us to investigate whether signaling through this specific part of the IL-6 gp130 receptor mediates reduced thymopoiesis with age. Our results will improve our understanding of the aging immune system and inform potential therapies

for regenerative medicine. Successful completion of these aims is a critical component of a comprehensive training plan, in which I will gain skills in experimental design, data analysis, scientific communication, and mentorship to grow as a future physician scientist. I will be supported by my sponsor, Dr. Gay Crooks, in a

collaborative training environment at UCLA.