Autophagy Differentially Regulates Tissue Tolerance of Distinct Target Organs in Graft-Versus-Host Disease Models

Authors

Katherine Oravecz-Wilson
Emma Lauder
Austin Taylor
Laure Maneix
Jeanine L Van Nostrand
Yaping Sun
Lu Li
Dongchang Zhao
Chen Liu
Pavan Reddy

Publication Date

3-1-2024

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI167369

PMID

38426503

PMCID

PMC10904048

PubMedCentral® Posted Date

3-1-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Mice, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Intestines, T-Lymphocytes, Epithelial Cells, Immunology, Transplantation, Autophagy

Abstract

Tissue-intrinsic mechanisms that regulate severity of systemic pathogenic immune-mediated diseases, such as acute graft-versus-host disease (GVHD), remain poorly understood. Following allogeneic hematopoietic stem cell transplantation, autophagy, a cellular stress protective response, is induced in host nonhematopoietic cells. To systematically address the role of autophagy in various host nonhematopoietic tissues, both specific classical target organs of acute GVHD (intestines, liver, and skin) and organs conventionally not known to be targets of GVHD (kidneys and heart), we generated mice with organ-specific knockout of autophagy related 5 (ATG5) to specifically and exclusively inhibit autophagy in the specific organs. When compared with wild-type recipients, animals that lacked ATG5 in the gastrointestinal tract or liver showed significantly greater tissue injury and mortality, while autophagy deficiency in the skin, kidneys, or heart did not affect mortality. Treatment with the systemic autophagy inducer sirolimus only partially mitigated GVHD mortality in intestine-specific autophagy-deficient hosts. Deficiency of autophagy increased MHC class I on the target intestinal epithelial cells, resulting in greater susceptibility to damage by alloreactive T cells. Thus, autophagy is a critical cell-intrinsic protective response that promotes tissue tolerance and regulates GVHD severity.

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