When an individual is challenged by a virus, a bacterium or any other infectious agent, several classes of white blood cells are being activated in order to fight the invasion.
One particular important class of white blood cells are the so-called T lymphocytes.These cells originate in the bone marrow and mature in the thymus, hence called ‘T' cells. Once matured, these cells circulate as naïve T cells throughout the body in an inactive form. In case of an infection, another class of white blood cells, macrophages and dendritic cells, can activate the T cells by presenting small peptides derived from these infectious agents to specific receptor molecules that reside on the surface of T cells, the so-called T cell receptors. Activation occurs within secondary lymphoid tissue such as the lymph nodes, through which both the dendritic cells harboring the foreign peptides as well as the T cells migrate. Once the T cell receptors are activated, T cells expand in numbers in order to be able to efficiently fight the infection from which the activating peptides were derived, hence the observed ‘lymph node swelling' upon an infection.
To be able to generate appropriate immune responses, a sufficient amount of naïve T cells has to circulate through the organism in order to be ready to become activated in case of an infection. How these naïve T cells are being maintained within the peripheral organs is poorly understood.
The new study from the Biozentrum, University of Basel is a follow up from earlier work, published 2007 in Cell. In that work, the researchers focused on a completely different question, namely how the notorious pathogen Mycobacterium tuberculosis can survive within macrophages. Several years ago, Jean Pieters and his colleagues, defined a protein, termed coronin 1 (originally named TACO) that they hypothesized to be an important host molecule that was hijacked or misused by M. tuberculosis in order to ensure its survival within the macrophage. To further investigate this hypothesis, Pieters and colleagues generated a mouse lacking coronin 1 expression. While in macrophages from these mice, as predicted, M. tuberculosis cannot survive, the mice did not show any other obvious phenotype.
‘It was however difficult to accept that coronin 1 was just there to help M. tuberculosis survive better' says Pieters, ‘and therefore we looked into any potential anomaly that these mice might harbor as an indication for the normal function of coronin 1'. The first hint on a potential role for coronin 1 came when the analysis of tail blood from mice lacking coronin 1 suggested that these mice harbored less T cells in their blood. Immediately, all available mice were analyzed in depth, indeed revealing a profound deficiency in peripheral T cells.
Since T cells have to mature within the thymus it was important to investigate whether the thymus in coronin 1 deficient mice was still able to produce T cells. In collaboration with Hans-Reimer Rodewald from the University of Ulm, Germany, and Ton Rolink and Rod Ceredig from the Department of Biomedicine, University of Basel, the researchers were able to define that nothing was wrong with T cell maturation in the thymus, leaving the option of a role for coronin 1 in peripheral T cell homeostasis and survival.
T cells are known to be very sensitive towards activation of their T cell receptors. While too much signaling can result in an overproduction of T cells, such as is the case in certain leukemia's, too little signaling may lead to
T cell death. Indeed, when the Basel researchers started to analyze signaling in T cells lacking coronin 1, they found a virtual absence of signal transduction downstream of the T cell receptor in T cells lacking coronin 1, resulting in an inability of coronin 1 deficient T cells to proliferate.