Daan Pieren

14 Chapter 1 investigation and a clear-cut phenotype has not been established. In mice, a subset of CD8 + Tregs has been characterized by expression of CD122 [63], the β -chain of the interleukin (IL)-2 and IL-15 receptors, and Programmed cell Death protein-1 (PD-1) [64]. These cells produced IL-10 as one of the mechanisms for their suppressive capacity [64,65], and showed increased suppression in the presence of IL-15 [64]. Additionally, the transcription factor Helios was reported to be required for the stabilization of suppressive functionality of CD8 + Tregs [66], potentially being an important hallmark for the characterization of CD8 + Tregs. In humans, several phenotypes have been reported to describe CD8 + Tregs, including CD8 + CXCR3 + T cells [67], and CD25 + FoxP3 + CD8 + T cells [68-70]. To date, CD8 + Tregs have been shown to prevent allograft rejection [64], accumulation of abnormally activated T cells [63], and experimental autoimmune encephalitis [71] in mice, the latter by suppression of autoreactive CD4 + T cells [72]. CD8 + Tregs have also been shown to increase with age in mice [52], although this is still unclear in humans, as studies show higher [69] and lower levels of CD8 + Tregs [73]. These differences are most likely due to the use of different markers to identify CD8 + Tregs. Thus, whether CD8 + T cells with immunosuppressive capacity accumulate with age and dampen protective T-cell responses remains to be explored. AGING WITH T CELLS: HOW DO T CELLS CHANGE? It is well known that aging results in a decline of immune functions throughout the immune system [22], collectively called ‘immunosenescence’. T cells are also subject to immunosenescence, as they show changes in their phenotype, and proliferative and activation potential [44]. Immunosenescence of T cells is used as a general term to describe two hallmarks that occur to T cells during aging: T-cell senescence and T-cell exhaustion ( Figure 2 ). Together, these changes are speculated to impair the T-cell response against infections, as has been shown in aged mice in primary [74-78] and secondary [79] T-cell responses against infection, and studies in humans showed similar results [80-82]. Thus, the development and accumulation of immunosenescent T cells during the process of aging is thought to be an important mediator for increased susceptibility to infectious disease in older adults. However, in-depth knowledge on how T cells alter during aging and whether this alteration causes susceptibility to disease is still lacking.