Defective CD8 Signaling Pathways Delay Rejection in Older Recipients

Abstract

CD8+ T cells play a cardinal feature in response to alloantigens and are able to generate effector/memory T cells independently from CD4+ T cells. To investigate the impact of aging on CD8 T cells, we used a fully mismatched mouse skin transplant model. Our findings showed a prolonged allograft survival in older recipients associated with a significant increase of CD4+ and CD8+ CD44high CD62Llow effector/memory T cells and a reduced systemic IFNγ production. When reconstituting young CBA Rag-1 mice that lack mature T and B cells with old CD8+ T cells expressing clonal anti-H2K T cell receptor (TCR) alloreactive for MHC I, graft survival was significantly prolonged and comparable to those receiving young CD8+ T cells. Moreover, our data showed that reduced systemic IFNγ levels observed in old recipients had been linked to a compromised expression of the IL-2R β subunit (CD122) by old CD8+ T cells. In addition, we observed an impaired IFNγ production on IL-2 receptor activation. At the same time, gene profiling analysis of old CD8 T cells demonstrated reduced chemokine ligand-3 and CD40L expression that resulted in compromised CD8+ T cell/dendritic cell communication, leading to impaired migratory and phagocytic activity of CD11c cells.Collectively, our study demonstrated that aging delays allograft rejection. CD8 T cells play a critical role in this process linked to a compromised production of IFNγ, in addition to a defective IL-2 receptor signaling machinery and a defective communication between CD8 T cells and dendritic cells.

Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus

“…Although TAC did not affect the composition of CD4 + T cell subpopulations, TAC inhibited cytokine production in an age-specific manner. In line with our previous studies (17,18), overall production of IFN-γ in splenocytes of old animals was significantly reduced compared to their young counterparts while frequencies of IFN-γ + CD4 + and CD8 + T cells were significantly elevated in old recipients. Although these findings may appear contradictive at a first glance, production of IFN-γ increased in parallel with an increased production of IL-10 in old animals.…”

“…In line with other groups, we found that aging is associated with a decline in naïve and increased frequencies of effector/memory CD4 + T cells both, in clinical and experimental models. (17,18,21) Thus, we assessed in-vivo, whether TAC administration altered CD4 + T cell populations. Following skin transplantation and TAC treatment, old mice exhibited higher frequencies of CD4 + CD44 high CD62L low effector/memory T cells while frequencies of naïve CD4 + CD44 low CD62L high T cells declined (Fig.…”

“…Elispot testing was performed as described previously. (17) Spots were determined by a computer-assisted enzyme-linked Immunospot image analyzer (Cellular Technology, Cleveland, OH, USA).…”

Aging and the immune response to organ transplantation

“…Depletion of CD8 + T cells via an anti-CD8 mAb administered to aged skin allograft recipients treated with anti-CD45Rb and anti-CD45 substantially enhanced allograft survival (>30 days), whereas it had no effect in young skin recipients (78). CD8 + T cells were implicated in another experimental skin allograft study in which CD8 + T cells isolated from mice aged 18 months induced a substantially (>20 days) slower tempo of skin allograft rejection after adoptive transfer into lymphodeficient hosts than CD8 + T cells isolated from young mice (79). Interestingly, in this study reduced expression of CCL3 and CD40L on aged CD8 + T cells was associated with reduced CD8 + T cell/DC interaction, indicating that alterations in aged CD8 + T cells may have important indirect effects on DC function.…”

“…Before transplantation, aged mice exhibit a reduced number of naive CD8 + T cells with similar numbers of effector and central memory T cells in the spleen (78), although the total numbers of memory CD8 + T cells are increased in aged mice (18 months of age) before transplantation (79,80). Aged mice (14-18 months) resist the skin allograft-promoting properties of anti-CD45Rb and anti-CD154, which robustly enhance fully MHC-mismatched skin allografts in young murine recipients (78,80).…”