Differential Impact of Autophagy on Innate and Adaptive Immune Cells Characterizes Alloimmune Responses in Aging

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IntroductionAging and chronic antigen exposure shape the balance of innate and adaptive immunity. We hypothesized that autophagy will impact the homeostasis of innate and adaptive alloimmune responses in an age-dependent fashion.MethodsA mouse model of sequential donor-specific and third party skin grafts was used to dissect innate and adaptive alloimmunity.ResultsYoung and old C57BL/6 recipient mice (2 and 18 mths, respectively) were sensitized with fully mismatched skin grafts from young DBA/2 mice. Graft survival following this set of transplants confirmed prolonged graft survival in old recipients (p=0.0195). Three weeks after the initial transplant, recipient mice were challenged with second skin grafts of either donor (DBA/2) or third-party (CBA/J) origin. Secondary donor-specific grafts accelerated rejection in both groups regardless of recipient age (p=0.0304). Notably, secondary third party grafts were rejected in a dramatically accelerated fashion in old but not young recipients (p=0.0198). Next, we transplanted an additional set of skin transplant recipients three weeks after the primary graft placement with a secondary F1 (C57BL/6-CBA/J) graft, presenting both ‘self’ and ‘non-self’ antigens. Graft survival of secondary F1 grafts was prolonged in in old recipients, supporting the relevance of innate over adaptive immunity with aging.As autophagy has been shown to be compromised in aging, we next probed the expression of major genes of autophagy induction (atg5, atg7, becn1, map1lc3a) in innate and adaptive immune cells. Intriguingly, autophagy levels mimicked the altered balance of innate and adaptive immunity detected in our skin graft experiments: while isolated old CD4+ T cells showed significantly lower baseline levels compared to young cells, innate immune cells displayed either age-independent (natural killer cells) or even increased levels in old monocytes.ConclusionCollectively, our results highlight a predominance of innate immune responses during an aging alloimmune response with a specific autophagy pattern, unraveling a new conceptual approach in understanding age-dependent graft survival and immunosuppression.

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