Myeloid reprogramming of T cells: a mechanism to maintain peritoneal homeostasis

Peritoneal leukocytes are essential for immunoregulation, tissue homeostasis and repair. When homeostasis is disturbed leukocytes are recruited to restore balance. Previously, we described the reprogramming of liver-resident CD8+T-cells upon interaction with neighbouring myeloid cells (Pallett_etal.,Nature_2023). Upon interaction, resident CD8+T-cells ‘steal’ plasma-membrane fragments, acquiring constitutive immunomodulatory features at rest and enhanced antiviral/antitumour capacity. These ‘super-responder’ myeloid-instructed CD8+T-cells can be detected by co-staining for CD8/CD14. In advanced chronic liver disease, fluid (ascites) can build up in the peritoneal cavity. We hypothesise that myeloid cells within the cavity reprogramme CD8+T-cells to help maintain peritoneal homeostasis, providing local antiviral/anti-tumour immunosurveillance. Co-staining for CD8/CD14 shows myeloid-instructed CD8+T-cells accumulating in ascites, correlating positively with acute-phase-protein (CRP) and negatively with disease severity (MELD). Myeloid-reprogramming enhances responsiveness to TCR-stimulation, increasing antimicrobial cytokine/chemokine production within their tissue niche. We also demonstrate that CD14+CD8+T-cells respond to viral peptide stimulation, with increased polyfunctional dual-cytokine producing (IFNg+TNFa+) cells. Furthermore, these cells produce more autocrine IL-2, likely to support their own proliferation and retention of a memory phenotype and can better mobilise cytotoxic granules upon antigenic encounter. Stealing of the LPS-receptor from myeloid cells also allows CD14+CD8+T-cells to respond directly to bacteria. We confirmed LPS-receptor internalization, indicating some cells may be 'seeing' LPS in vivo. CD14+CD8+T-cells take up significantly more LPS than their CD14-negative counterparts in an LBP-dependent manner, indicating a role for the LBP rich physiological environment. By their polyfunctional role, myeloid-instructed CD8+T-cells may contribute to the maintenance of immune homeostasis, representing an important immune sentinel providing critical antiviral/antitumour and antibacterial immunosurveillance.

Publication History

Article published online:
20 January 2025