Age-associated Senescent - T Cell Signaling Promotes Type 3 Immunity that Inhibits Regenerative Response

Abstract

Aging is associated with immunological changes that compromise response to infections and vaccines, exacerbate inflammatory diseases and could potentially mitigate tissue repair. Indeed, regenerative medicine strategies designed to promote tissue repair are now focusing on the immune system as a therapeutic target due to its role in response to tissue damage and regulation of tissue repair. However, age-related immune changes to the response to damage and the resulting impact on repair remains unknown. Here, we characterized age-related immunological changes that inhibit tissue repair and therapeutic response to a clinical regenerative biological scaffold derived from extracellular matrix (ECM). We found that aging reduced the response of interleukin (IL)4 producing eosinophils and CD4 T cells in a volumetric muscle injury treated with ECM leading to reduced repair and increased fibrosis. Single cell RNA sequencing and cell-cell communication analysis via transcription factor (TF) activation revealed diminished interactions between immune and stromal modules in aging animals. Validation of the age-specific TFs and predicated protein interactions in the tissue and draining lymph nodes found multiple genes activated in old animals only after injury that were primarily related to IL17 signaling. Local inhibition of age-related type 3 immune activation using IL17-neutralizing antibodies restored therapeutic response to ECM and promoted muscle repair in older animals through increased recruitment of IL4 producing immune cells and regenerating muscle fibers. Altogether, innate and adaptive immune changes that occur with aging, in combination with dysregulated stromal communication, contribute to an impaired response to tissue injury which can be overcome with combination immunotherapy.

The foreign body response: emerging cell types and considerations for targeted therapeutics

“…Recent work has detailed the role of T lymphocytes in the response to a biological scaffold and found that aging induces senescence and increases IL-17-related signaling that impairs tissue repairs and therapeutic responses to biological scaffolds. 184 These studies raise the importance of age-specific innate and adaptive immune responses to biomaterials, including context-specific macrophage responses, and their implication for limiting the foreign body response.…”