White et al  image 2
Newly-produced T-cells (in blue) are prevented from leaving thymic tissue, having accumulated in the perivascular space (in red).

Recent research led by the University of Birmingham has shown that iNKT-cells, a T-cell subset with limited diversity, act as cellular gatekeepers to control the exit of highly variable alpha-beta T-cells (abT-cells) from the thymus. 

The thymus is an essential organ for controlling the production of T-cells, which are important in immune responses against viruses and bacteria. In the thymus, the medulla acts as a repository for newly produced T-cells. It also represents the exit point from the thymus, so that new T-cells can leave the thymus to circulate around the body.

Although exit from the thymus is seen as a critical stage in the formation of a functional immune system, the mechanisms controlling this process are poorly understood, and very few regulators are known.

In this study, the cover story of the August edition of The Journal of Experimental Medicine, led by Professor Graham Anderson and Dr Andrea White from the University of Birmingham’s Institute of Immunology and Immunotherapy, the team examined how T-cells leave the thymus.

‘As well as producing new T-cells, the thymus must also release them into the body so that they can patrol and seek out invading pathogens,’ explains Professor Anderson. ‘If this process does not operate correctly, T-cells may be limiting in body tissues which may weaken subsequent immune responses’.

Their study describes a novel mechanism for thymus exit, in which production of the type 2 cytokines IL4 and IL13 by iNKT-cells triggers the surrounding thymic microenvironment to release conventional abT-cells into peripheral tissues. If this axis is perturbed, either by the absence of iNKT-cells or their products, abT-cells build up within the thymus and are not able to access peripheral tissues correctly.

‘In our study, we set out to examine how the thymus controls the exit of highly diverse abT-cells, as these cells are a fundamental component of effective immunity,’ says Professor Anderson.

‘We found that this process is controlled by another type of abT-cell, iNKT-cells, that are much less diverse. This is surprising as it demonstrates for the first time that different kinds of abT-cell regulate an important component of thymus function, namely T-cell exit. So, for conventional abT-cells, they get by with a little help from their friends’.

The group is now interested in determining the downstream molecules that iNKT-cells trigger that mediate thymic exit, to gain a better understanding of thymus and immune system function.