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

Resident memory T cells (T(RM)s), 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(RM)s 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(RM)s 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(RM)s after injury. Our results suggest a nonantigen-specific or antigen-independent mechanism capable of generating T(RM)s in the kidney and highlight the need to better understand T(RM)s and their involvement in CKD.NEW & NOTEWORTHY Resident memory T cells (T(RM)s) 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(RM)s and the processes by which they can differentiate independent of antigen may help our understanding of the interactions between the immune system and kidneys.