Mechanisms and novel targets of T-cell Immunity in Aging

Abstract Organ transplantation is the treatment of choice for end-stage-organ failure. Notably, older patients (>65 years) have shown the highest increase of those either waiting for, or having received, organ transplants. Clinically, acute rejections are more challenging to treat in older recipients while chronic rejections are more frequent. At the same time, older recipients have higher rates of infections and malignancies. Rather than generally impairing immune responses, aging affects immune compartments and functions in specific ways. Thus, aging has clinically most relevant consequences on transplant outcomes with effects on alloimmune responses that are only marginally appreciated. In addition, effectiveness and side-effects of immunosuppression are modified in older recipients. Of particular relevance, aging limits the immunoregulatory capacity of co-stimulatory blockade. Our previous studies have detailed the consequences of aging on alloreactive T cells including CD-4, CD-8 and regulatory T-cells. Aging also affects T cell metabolism with a compromised mitochondrial oxidative phosphorylation that is not compensated by aerobic glycolysis in old CD4+ T cells, thus initiating a reliance of old CD4+ T cells on glutaminolysis for their proliferation and activation. From a therapeutical perspective, inhibition of glutamate metabolism in CD4+ T cells specifically prolonged graft survival in older recipients. Of additional relevance is that players of the innate and adaptive immune response are affected differently by aging. Here, we observed an activation of old donor DCs through the release of cell-free mitochondrial DNA (cf-mt-DNA) originating from senescent cells that accumulated in old organs leading to an intensified Th17 response. Clearly, aging has broad effects on cellular and immunosenescence representing two distinct but interrelated pathogenic processes. However, mechanisms driving the interaction of cellular immunity with alloimmune responses in older recipients are not understood and may provide an opportunity to refine treatment while identifying novel therapeutic targets. We are uniquely positioned and have accumulated an extensive body of preliminary and published data in aging and organ transplantation. As our central hypothesis, we submit that aging rewires alloimmunity with critical effects on allorecognition, DC/T cell interaction, and T cell metabolism. As a corollary hypothesis we submit that cellular senescence augments alloimmunity and that a targeted delivery of nanoparticles will provide novel opportunities for a refined immunosuppression in older recipients. In Aim 1, we will delineate mechanisms by which DCs of aged recipients regulate T cell alloimmunity. Aim 2 will detail T-cell metabolism and age-specific regulation of critical alloreactive T cells. Aim 3 will develop an effective age-specific immunosuppression through nano-delivery of glutamine inhibitors and senolytics to DLNs restoring the immune regulatory capacity of co-stimulatory blockade.