Aging has a complex effect on immune responses (6
). One consistent effect is that aging leads to an accumulation of memory T cells (5
), even though a prior study indicated that the function of memory T cells declines with aging (27
). Based on these studies, we predicted that aged hosts would exhibit increased numbers of donor-specific effector memory responses, characterized by rapid IFN-γ secretion (24
), as compared to young hosts, prior to transplantation. However, our study found that that aged hosts exhibited augmented donor-specific, effector memory IL-17, but not IFN-γ, responses prior to transplantation compared to young mice. We showed that CD4+
memory T cells are responsible for the elevated alloimmune response with aging, a phenotype that may be exacerbated by weaker IL-2 alloimmune responses. Importantly, we demonstrated that the heightened IL-17 allommune responses contributed to acute allograft rejection in aged transplant recipients. Our results indicate that aging elevates memory IL-17 alloimmune responses.
IFN-γ producing donor-specific memory T cells, predominantly of the effector memory phenotype, may be an indicator of an increased tendency toward acute allograft rejection (28
). Based on our results, IFNγ measurement may not be sufficient for indicating the presence of donor-specific memory responses with aging. Our work suggests that IL-17 may be a more reliable indicator of the presence of cross-reactive effector memory T cells in aged recipients. This is particularly relevant to solid organ transplantation, for which the fastest growing cohort of patients awaiting transplantation is greater than 65 years of age. Our results await validation using human cells.
Prior studies have associated increased systemic IL-6 levels, a Th17 promoting factor, with aging (29
). Furthermore, aging is associated with an increased number of regulatory T cells (19
), which can act as a source of TGF-β, another Th17 promoting factor (30
). In contrast, it is well known that aging leads to reduced IL-2 responses, a negative regulator of the Th17 pathway (4
). Apparently, with aging there are increases in Th17 promoting factors and a reduction in Th17 regulatory factors. Thus, it is plausible that, with aging, CD4+
T cells may transition to a Th17 phenotype upon exposure to environmental antigens. Some of these CD4+
T cell effectors may then differentiate into IL-17 producing memory T cells, which may cross-react with alloantigens. This may explain why the IL-17 T cell alloimmune response in young mice was lower than that in aged mice after immunization with alloantigens. Young hosts may not be prone to IL-17 immune responses. Future studies will be required to mechanistically examine how aging leads to accumulated numbers of IL-17 producing memory CD4+
Our study shows that aged hosts exhibit increased numbers of memory CD4+
T cells that produce IL-17 when stimulated with donor alloantigens. These memory cells could present a barrier to transplantation. However, since aged hosts have increased numbers regulatory T cells (19
), which may aid in immune tolerance induction, it is not clear how age will affect the application of protocols that induce transplantation tolerance. This will clearly be an important topic for future investigation.
In contrast, a previous report found that aged recipients exhibit increased IFNγ and IL-2 responses after transplantation (32
). However, a major difference between that study and ours is that acute rejection in the prior study was abrogated by the use of cyclosporine. Clinically, this distinction may be relevant, because several clinical studies have documented an association of increasing recipient age with reduced rates of acute allograft rejection (9
). In contrast, aging reportedly leads to increased chronic rejection (33
). Given the recent findings that IL-17 may contribute to chronic lung rejection (34
), it will be important for future studies to determine whether heightened IL-17 alloimmune responses with aging impact the development of chronic rejection.
Our study provides evidence that aging leads to elevated IL-17 alloimmune responses that can influence the rate of acute allograft rejection in individuals. When translated to the clinic, this information may be important for tailoring therapies to treat acute allograft rejection in older transplant recipients.