NIH awards the University of Connecticut $3.5 million over five years to grow thymus cells from reprogrammed cells of older people, aiming to restore an organ whose output of immune T cells declines with age

NIH awards the University of Connecticut $3.5 million over five years to grow thymus cells from reprogrammed cells of older people, aiming to restore an organ whose output of immune T cells declines with age

On October 12 the university announced that research professor Laijun Lai has received a grant from the US National Institutes of Health (NIH). His laboratory will transplant these cells into old mice and test whether they support the development of human T cells.

The thymus begins to atrophy in infancy. Its epithelial tissue is gradually replaced by fat, and its output of new T cells halves roughly every 16 years, according to an estimate in a 2018 paper in PNAS. The university calls this atrophy a root cause of the decline in immunity with age. A virus that gives a young person a cold lasting a few days can cause a life-threatening illness in an older person, and vaccines work less well.

Naive T cells, which have not yet encountered an antigen, mature in an environment created by thymic epithelial cells (TEC). Cortical TEC select the cells that are able to function, and medullary TEC remove the cells that target the body's own tissues. With age, TEC become fewer and work less well, and the university considers this one of the main reasons the thymus declines.

The age of a naive helper T cell affects immune memory. In a 2003 study in mice, Laura Haynes, a co-investigator on the grant, and her colleagues showed that memory formed from the cells of young mice still responded well a year later, while memory formed from the cells of old mice responded weakly.

In a 2015 paper, Lai's laboratory described a protocol that turns human embryonic stem cells into TEC precursors using the proteins HOXA3 and FOXN1. Mice lacking the genes for these proteins do not develop a thymus. When transplanted into mice, the precursors became cortical and medullary TEC, and after 24 weeks mouse T cells were developing in the transplanted tissue. When human blood-forming cells (the cells that give rise to T cells) were transplanted together with the precursors, functional human T cells also appeared.

Lai is now replacing embryonic cells, which are foreign to the recipient, with induced pluripotent stem cells (iPSC). These are made by reprogramming the patient's own cells. Like embryonic cells, they can turn into many cell types, and the body rejects them less often. The cells of an older person have aged, but French researchers showed in 2011 that reprogramming resets the marks of age. iPSC made from the cells of centenarian donors matched embryonic cells in telomere length (the ends of chromosomes) and in gene activity, and the cells grown from them were rejuvenated.

The project, funded by the National Institute on Aging, tests whether thymus cells derived from the iPSC of older people can create, in an old body, an environment where new T cells mature. The laboratory will derive TEC precursors from iPSC and transplant them, together with human blood-forming cells, into old immunodeficient mice that do not reject human cells. The researchers will count the TEC and the new T cells, assess how well they function (according to the university, this includes infecting the animals with influenza virus), and check whether the T cells target the body's own tissues.

In separate experiments with mouse cells, the laboratory will determine which developing T cells help TEC mature. According to the grant application, in preliminary experiments growing the precursors together with developing T cells helped them become TEC.

“There are currently no approaches that address T-cell immunodeficiency in older adults,” says Lai.