The thymus is the powerhouse producing the immune system’s T cells, which combat infection in our body.
Yet this vital organ is one of the first to diminish in function as we age, resulting in a gradual loss of T cell production and eventually increased susceptibility to infections and cancer in the elderly.
Monash Biomedicine Discovery Institute (BDI) researchers have for the first time identified factors affecting the cells in the thymus that set in motion this loss and the mechanisms behind this.
Their study, published in Cell Reports today, paves the way to develop targeted strategies for the recovery of T cells to help combat infections and cancers.
Associate Professor Ann Chidgey, senior author, said it had been known for some time that the thymus – a small organ located below the collarbone – degenerated from puberty onwards.
However, the mechanisms underlying this were unclear.
“Our thymus is most productive soon after birth and produces a full repertoire of T cells, but then slowly begins to lose function.
As we live longer, the diversity of our T cells diminishes and we become more susceptible to infections,” she said.
“It also becomes more difficult to recover our T cell immunity after damage from cancer treatments such as chemotherapy which destroy a lot of our immune cells.”
The study showed what was behind this degeneration; factors affecting the epithelial stem cells in the thymus.
“This study identifies BMP4 and Activin, as growth and differentiation factors important for the self-renewal and differentiation of thymic epithelial stem cells, and how a change in their production during ageing causes a loss of mature epithelial cells.
This leads to a reduced capacity to support the production of T cells,” Associate Professor Chidgey said.
“This is the first time anyone has identified the basis for mature thymic epithelial cell loss and the molecules that are involved in the dysfunction of the thymic epithelial stem cells in ageing.
By doing this we can now focus on how to reverse that and ‘switch on’ the thymus again, even just transiently, to replenish our T cell diversity,” she said.
“We believe these changes can be reversed and are beginning new investigations to see if we can develop a treatment focussed on thymic epithelial cell regeneration.”
The selection of a functional and self-tolerant T cell repertoire is coordinated by multiple selection processes that occur during T cell development in the thymus; including positive selection, negative selection, and agonist selection.
While positive selection ensures that the T cell repertoire is functional and equipped to make robust responses against foreign antigens, negative selection and agonist selection make significant contributions to enforcing self-tolerance.
Distinct thymic microenvironments differ in their ability to support each of these selection events.
Thus, the ability of thymocytes to access these discrete microenvironments is a key factor in regulating thymocyte maturation, and ultimately in determining thymocyte fate.
The thymus is comprised of two distinct anatomical sites: the cortex and the medulla.
Each of these regions is populated by distinct subsets of thymic resident cells, creating microenvironments that are unique to each site and are specialized to coordinate distinct selection events.
For example, expression of a distinct proteasome subunit and unique lysosomal proteases within cortical epithelial cells generate a specialized peptide repertoire to support positive selection.
In contrast, a program of promiscuous gene expression in a subset of medullary thymic epithelial cells and ample expression of costimulatory ligands in the medulla make this locale particularly well suited to promoting negative selection (1).
The location of developing T cells within the thymus is tightly linked to their developmental stage. T cell progenitors enter the thymus through blood vessels at the corticomedullary junction and then subsequently localize to the outer regions of the thymic cortex, where they undergo rearrangement of the T cell receptor (TCR) α and β loci.
Cortical DP thymocytes that experience αβTCR signals in response to self-peptides presented by Major Histocompatibility Complex proteins (MHC) can undergo positive selection, resulting in maturation and commitment to either the CD4 or CD8 lineage, depending on whether the selecting MHC was class II or class I, respectively (5).
Positive selection also leads to the relocalization of thymocytes from the cortex to the medulla, and the majority of medullary thymocytes exhibit a CD4+CD8− or CD4−CD8+ “single positive” SP phenotype.
After several days of further maturation in the medulla, SP thymocyte become competent to leave the thymus as fully functional mature T cells (6).
Thymocyte motility is key both to orchestrating migration between different thymic microenvironments at the appropriate developmental stage, and also to shaping the TCR signaling pattern experienced by thymocytes upon encounter with self-peptide MHC complexes in the thymus.
In the past several years, our lab has been focused on the inter-relationship between thymocyte motility and T cell repertoire selection in the thymus.
Most recently, we have been making extensive use of a thymic slice preparation that greatly facilitates direct visualization of T cell development using 2-photon microscopy, and has also proved to be a powerful system for synchronizing and manipulating T cell development.
In this review, we will discuss some of our key findings using this approach, placing them in the context of other advances in the field.
More information:Cell Reports (2019). DOI: 10.1016/j.celrep.2019.05.045, http://dx.doi.org/10.1016/j.celrep.2019.05.045
Journal information: Cell Reports
Provided by Monash University