International Journal of Nephrology 3 Heart ↑ TNFα, IL-1 ↑ Neutrophil traﬃcking ↑ Apoptosis Brain AKI Liver ↑ Leukocyte inﬂux ↑ Oxidation products ↓ Antioxidants (GSH) Altered liver enzymes †A brain IL-8 homologue ∗Granulocyte colony-stimulating factor †Glial ﬁbrillary acidic protein Glutathione ↑ Chemokines KC† and G-CSF∗ ↑ GFAP‡ and microglia ↑ Vascular permeability Lungs ↑ Vascular permeability ↑ Cytokines/chemokines ↑ Leukocyte traﬃcking Transcriptomic changes Gut ↑ Channel-inducing factor ↑Potassium excretion Figure 1: AKI and organ crosstalk. AKI induces remote organ injury in the heart, brain, lungs, liver, and gut involving multiple inﬂammatory pathways, including increased expression of soluble proinﬂammatory mediators, innate and adaptive immunity, cellular apoptosis, physio- logic derangements and genomic changes. by decreasing the inﬁltration of T cells, dendritic cells, and macrophages [23]. T cells may act during early IRI despite lacking alloanti- genic stimulation, which challenges the traditional function of T cells as exclusive mediators of the adaptive immune response [19]. Signiﬁcant evidence exists to support the role of T cells in gut, heart, and lung ischemia-reperfusion injury [24–28]. Likewise, experimental data also points toward antigen-independent T-cell activation in ischemic AKI through cytokines secreted by macrophages and den- dritic cells, chemokines, oxygen free radicals and the com- plement system [7, 19, 29]. Speciﬁc populations of T cells likely contribute to injury in unique ways. For example, mice deﬁcient in CD4+ and CD8+ cells and athymic mice demonstrate protection from experimental ischemic AKI; however, only adoptive transfer of T cells of the CD4+ type restores this injury [30, 31]. Not all T cells, however, perpetuate inﬂammatory damage during ischemic AKI; some populations of T cells confer renal protection after IRI, particularly the Th2 phenotype of CD4+ T cells and T regulatory cells [32]. Additional recent experimental data has characterized speciﬁc populations of T lymphocytes traﬃcking to remote organs that may facilitate organ crosstalk during ischemic AKI. In a rodent model of kidney IRI, a distinct inﬂux of CD3+ (T) cells with a predominant CD8+ T cell subpopulation was identiﬁed 24 hours after experimental kidney IRI. These pulmonary T cells acquired increased expression of activation markers suggesting that ischemic AKI induced traﬃcking of activated T cells which contributed to pulmonary injury, speciﬁcally apoptosis [33]. The speciﬁc role of subpopulations of T cells in the pathogenesis of ischemic AKI remains a stimulating topic of current and future investigation, both in the innate and adaptive immune response to kidney IRI. 2.2. Adaptive Immunity. The adaptive immune system relies on the speciﬁcity of antigen receptors on both B and T cells that respond to millions of various antigenic molec- ular structures. Once stimulated by an antigen, B cells (humoral immunity) produce speciﬁc antibodies, perform opsonization to facilitate phagocytosis, and activate the complement system. The T-cell receptor (TCR) responds to presented antigen peptides by activating macrophages to kill phagocytosed microbes, directly destroying infected cells and by releasing cytokines to promote further response (cell- mediated immunity). Antigen-dependent T-cell activation has been demon- strated in experimental models of renal IRI [34, 35]. For example, mice with a restricted TCR cell repertoire suﬀer