Loss of thymic FoxN1 mimics age-related immune decline

Researchers at the University of Texas use ProImmune Pro5® MHC Class I Pentamers to measure antigen-specific immune responses in an artificial mimicry of aging.

Guo, J., et al. (2012). Deletion of FoxN1 in the thymic medullary epithelium reduces peripheral T cell responses to infection and mimics changes of aging. PLoS One. 7(4): e34681. [PubMedID: 22514652]


Aging has long been associated with a decreasing overall effectiveness of the immune system and an impaired immune response to infection, resulting in higher viral loads, more severe symptoms, and increased disease mortality. One factor held responsible for decreased immune effectiveness is a marked age-related decline in the frequency of T cells. T cell precursors mature in the thymus, which begins to atrophy after puberty (termed “thymic involution”), thus older individuals have a limited capacity to produce mature T cells.

Jianfei Guo and his colleagues at the University of Texas investigated the role of forkhead-class transcription factor FoxN1 in the process of thymic involution, to see if loss of this protein would mimic age-related changes in immunity. 

FoxN1 is known to be essential for maintenance of the internal architecture of the thymus, and to regulate the development, differentiation, and function of thymic epithelial cells (TEC). In turn, TEC foster the maturation of thymocytes and are responsible for maintaining T cell numbers.


Dr Guo and his coworkers compared the immune response of mice engineered with a TEC-specific progressive loss of FoxN1 to age-matched wild-type mice and to an aged wild-type group. Prior to infection with influenza virus, all three groups had similar numbers of CD8+ T-cells.

The team used influenza-specific ProImmune’s MHC class I Pro5® Pentamers to analyse lung and spleen samples by flow cytometry. Ten days after infection, they found a 50% reduction in CD8+ T-cell frequency in aged mice and in mice with the FoxN1 deletion, compared to the young control mice. They further showed that the FoxN1-deficient mice suffered significant increases in lung injury, weight loss, and mortality as a result of the influenza virus compared to the control group, results paralleling those from the aged wild-type mice.

Progressive loss of FoxN1 resulted in accelerated thymic involution, while intrathymic injection of FoxN1 cDNA into aged wild-type mice was sufficient to increase their thymus sizes and thymocyte numbers.

Although it had previously been known that FoxN1 is essential for normal prenatal development of the thymus, this study provides the first evidence that it is also required for ongoing maintenance of T-cell function in the postnatal immune system. The study also showed that deletion of FoxN1 purely from TEC is sufficient to cause whole-body T cell impairment in infection response which mimics that observed with aging.

The results of this study have important medical implications, since humans experience the same decrease in effectiveness of the immune system with age as mice do. Older people are significantly more susceptible to pathogens such as influenza viruses. The study authors suggest further research into how peripheral T cells are affected by FoxN1 is required to understand fully the phenomenon of age-related decline in immune function.