Background Tissue injury with progressive damage is a major cause of morbidity and mortality in SLE. Yet, there is limited knowledge of the mechanistic pathways that contribute to tissue injury in lupus. We hypothesize that local environmental factors dictate effector function of tissue-infiltrating immune cells in target organs in SLE, to initiate and sustain damage, with therapeutic targeting of these maladaptive changes able to reverse damage. Our hypothesis is based upon the idea that local microenvironment naturally responds to stress or insult, such as mediated by glomerular immune complex deposition or environmental damage to the skin, with changes in the local microenvironment affecting immune-cell phenotype and function.

Methods and Results To identify tissue-adaptive pathways mediated by the local microenvironment that initiate and sustain organ injury, we dissected tissue-infiltrating T cells in the lupus kidney, building upon the longstanding observation that T effector cells are necessary for the local inflammatory response. For example, tissues become hypoxic as a common denominator as an appropriately physiologic response occurring at sites of pathogen replication or in tumors to ensure lymphocyte survival and effector function. The kidney, naturally hypoxic at the corticomedullary junction and in the medulla, becomes even more hypoxic during inflammation. We demonstrated that upon renal infiltration, T cells adapt to the hypoxic environment, without exhaustion, to ensure their survival and effector capability, with remodeling of metabolic and epigenetic pathways with tissue damage driven by a hypoxia-dependent, transcriptionally regulated inflammatory gene program. Tissue hypoxia was initiated by autoantibody-dependent glomerular immune complex formation, with subsequent renal entry of T cells that environmentally adapt with tissue-damaging effector function of a type 1 (Th1 or Tc1) phenotype. Survival was sustained by genetic and metabolic reprogramming of CD4⁺ and CD8⁺ T cells, including alteration in cell death and energy utilization pathways. Selective genetic, or more practically, pharmacologic blockade of tissue-adaptive pathways dampened activated T-cell function, reversing tissue hypoxia and alleviating established damage. The same pathways are operative in human lupus nephritis.

Conclusions We demonstrate that upon infiltration into the kidney, T cells adapt to the local environment to ensure their survival and effector capability, with remodeling of metabolic pathways. Although beneficial to the host upon local pathogen invasion, such changes in lupus are maladaptive, leading to tissue damage. Understanding phenotypic changes in renal-infiltrating immune cells can lead to therapeutic targeting with disease amelioration.

Acknowledgements Supported by a Pilot & Feasibility Grant from the George M. O’Brien Center for Kidney Research at Yale (NIH P30 DK079310, J.C.), grants from the NIH R37 AR40072 (J.C.), R01 AR074545 (J.C.), and R21 AI142145 (J.C), NIH U19 AI082724 (M.R.C), and AbbVie (J.C.). P.M.C. was the recipient of government scholarship for graduate study from the Ministry of Education, Taiwan, and Gershon Fellowship from the Department of Immunobiology, Yale University.