Cognate antigen-independent differentiation of resident memory T cells in chronic kidney disease

Resident memory T cells (T_RMs), which are memory T cells that are retained locally within tissues, have recently been described as antigen-specific frontline defenders against pathogens in barrier and nonbarrier epithelial tissues. They have also been noted for perpetuating chronic inflammation. The conditions responsible for T_RM differentiation are still poorly understood, and their contributions, if any, to sterile models of chronic kidney disease (CKD) remain a mystery. In this study, we subjected male C57BL/6J mice and OT-1 transgenic mice to five consecutive days of 2 mg/kg aristolochic acid (AA) injections intraperitoneally to induce CKD or saline injections as a control. We evaluated their kidney immune profiles at 2 wk, 6 wk, and 6 mo after treatment. We identified a substantial population of T_RMs in the kidneys of mice with AA-induced CKD. Flow cytometry of injured kidneys showed T cells bearing T_RM surface markers and single-cell (sc) RNA sequencing revealed these cells as expressing well-known T_RM transcription factors and receptors responsible for T_RM differentiation and maintenance. Although kidney T_RMs expressed Cd44, a marker of antigen experience and T cell activation, their derivation was independent of cognate antigen-T cell receptor interactions, as the kidneys of transgenic OT-1 mice still harbored considerable proportions of T_RMs after injury. Our results suggest a nonantigen-specific or antigen-independent mechanism capable of generating T_RMs in the kidney and highlight the need to better understand T_RMs and their involvement in CKD.NEW & NOTEWORTHY Resident memory T cells (T_RMs) differentiate and are retained within the kidneys of mice with aristolochic acid (AA)-induced chronic kidney disease (CKD). Here, we characterized this kidney T_RM population and demonstrated T_RM derivation in the kidneys of OT-1 transgenic mice with AA-induced CKD. A better understanding of T_RMs and the processes by which they can differentiate independent of antigen may help our understanding of the interactions between the immune system and kidneys.