Tissues such as the skin, lungs, and the gastrointestinal tract act as barriers against invading pathogens. To protect the individual host, invading pathogens must be efficiently and quickly controlled by the immune system. In order to control pathogens with efficiency, one of the hallmarks of the adaptive immune system known as memory provides long-term protection of lymphocytes that easily recognize pathogens to rapidly clear them from the tissues. Cells in the immune system that partake in memory are known as long-lived CD8+ memory T cells, which include central memory (TCM) and effector memory (TEM) cells. TCM cells circulate through secondary lymphoid organs while TEM cells circulate through non-lymphoid tissues. Some of these memory T cells migrate into peripheral tissues, including skin, lung, and gastrointestinal tract, and become resident long-lived memory T cells (TRM) that protect against infection by taking up residence within the peripheral tissues. The underlying mechanisms and signals that regulate the retention of TRM cells in the tissues are not completely understood so scientists in a recent study looked at the effects of the TGF-b signaling on TRM cell migration to the gut tissues as well as TGF-b signaling while TRM cells reside in the gut tissues.
An important point to know is that the TEM cells develop a gut-homing capacity during local and systemic infections that upregulate a bunch of integrins for the T cells to settle into the gut. The T cells in the spleen upregulate the expression of a4b7 integrin that would allow the T cells to settle into the gut. When the T cells are inside the lamina propria or intraepithelial lymphocyte compartment (both are structural tissues of the gut), the T cells downregulate the integrin a4b7. As a result of residing in the gut, the T cells upregulate CD103 (integrin aE), CD69, and integrin a1 leading the T cells to being TRM cells. The scientists noted that a lack of CD103 (integrin aE) expression leads to less T cells residing in the gut. Given that, the scientists think the 3 proteins’ expression leads to the T cells staying in the gut. The scientists realized TGF-b can increase the expression of CD 103 in the gut on CD8+ T cells to a great extent. TGF-b (Transforming Growth Factor Beta) normally works to differentiate Th17 and Tregs, but it also has many other functions. The scientists believed TGF-b signaling is important for the retention of intestinal TRM cells so they used an experiment to show the regulation of TGF-b on TRM cells.
To showcase regulation of the TGF-b, the scientists came up with a model of a mouse that contains a control and a non-functional TGF-b receptor they called Tgfbr2-/- on the CD8+ T cells specific for the glycoprotein epitope of the virus LCMV. The model is carried out with an acute infection of the virus popularly known as Armstrong as well as the chronic infection known as Clone 13 so that the scientists could see any differences in numbers of T cells in acute versus a chronic infection for the migration of the TRM cells because they already know that the CD8+ T cells express an increased amount of the TGF-b receptor in chronic LCMV infection. When the scientists wanted to see the effect of the chronic LCMV infection on the T cells in the spleen, the T cells with the non-functional Tgfbr2-/- receptor increased the expression of a4b7 to move easier to the gut while in the absence of TGF-b signaling so this means that the signaling of TGF-b holds the normal T cells in the spleen, but more importantly a4b7 allows gut migration from the spleen while TGF-b is absent. The expression of a4b7 in chronic infection also means that the T cells are continuously supplied to the gut where the infection is occurring. Ultimately, TGF-b signaling greatly inhibited the expression of a4b7 integrin in normal T cells allowing Tgfbr2-/- CD8+ T cells a greater capability to migrate to the gut.
In comparing the chronic infection to the acute, the scientists noticed the number of T cells in the gut of the acute infection declined even with the presence of the normal TGF-b receptor that would normally allow the expression of the CD103 to increase to allow the T cells to reside. After careful comparison to the chronic infection past the 8 days, the chronic infection persisted so chronic infection required more non-functional TGF-b receptor T cells to continually migrate and be supplied after 8 days. During acute, the scientists concluded that the infection was cleared after 8 days, which meant the TRMs were not needed after the pathogens cleared. Thus, without continuous T cells, or any pathogens that need to be cleared, the control TRMs disappeared from the gut explaining the decline in TRMs.
Lastly, the scientists wanted to see the effect of clearing the virus within the chronic infection to back up their conclusion of the acute clearance. By clearing the IEL compartment after 2 months, the virus population as well as the virus antigens should decline upon clearing the infection as well as the T cells that have gut-homing capability. As a result, the scientists found out the Tgfbr2-/- T cells that could easily migrate became reduced compared to the control of normal TGF-b signaling because the pathogen cleared the infection so the gut did not need those T cells, but more importantly the Tgfbr2-/- T cells easily left the gut and did not reside in the gut so TGF-b is required to reside in the gut.
From the experiment, the signaling of TGF-b in the spleen inhibits the upregulation of a4b7 integrin meaning loss in gut-homing capability. Tgfbr2-/- T cells lost the capability to upregulate CD103 in the intestine as a result of no TGF-b regulation. In acute infection, the TRM cells reside for a shorter period of time compared to the chronic infection with prolonged migration to the gut. In the gut tissues, TGF-b is required for the retention of TRM cells to induce the integrins CD103, a1, and the protein CD69. It would be interesting to follow up the research with an experiment where the T cells TGF-b receptors remain functional, but the TGF- b signal in the environment is absent since the researchers only manipulated the receptor of the memory T cells.