Tissue and cellular mechanisms regulating T-cell exhaustion and the response to checkpoint immunotherapy

Abstract: Over a decade ago, researchers first characterized T cell exhaustion as the dysfunction and eventual depletion of antigen-specific T cells in mice during chronic viral infections. Subsequently, T cell exhaustion has been observed in diverse animal models and in humans facing chronic infections caused by viruses, bacteria, parasites, and in individuals with cancer. While the specifics of T cell dysfunction may vary depending on the particular pathogens involved, a common phenotypic and functional profile of T cell exhaustion is becoming increasingly evident. There has been considerable interest in restoring T cell function, particularly in human cancers.
The success of checkpoint immunotherapy in reinvigorating exhausted CD8+ T cells (Tex cells) relies on the activation of precursor cells known as exhausted T cells (Tpex). However, there is limited understanding of tissue context in which these Tpex cells are maintained, differentiated, and their interactions with other cells take place. In our study, we have identified distinct subpopulations of Tpex cells at the transcriptional level, delineated their differentiation trajectories as they transition into Tex cells, and associated this process to specific locations within the spleen where these cellular states are sustained. Conventional dendritic cells (cDCs) have been identified as crucial for the success of αPD-L1 therapy and for mediating viral control. While cDC1s were not essential for expanding Tpex cells, they played a vital role in providing a niche that supports the maintenance of Tpex cells. This niche prevented overactivation of Tpex cells and consequent T-cell-mediated immunopathology. Our findings reveal the pivotal role of cDC1s in preserving and safeguarding Tpex cells within specific anatomical niches. This intricate regulation helps maintain a balance between viral control, prevention of T-cell exhaustion, and avoidance of immunopathological responses.

In addition to our first study investigating how cellular interactions and tissue environments contribute to exhaustion, our research aimed to uncover metabolic cell-intrinsic mechanisms that drive T cell differentiation in the context of chronic antigen stimulation. Using a combination of genetically modified mice, single-cell transcriptomics, and metabolomic analyses, we have identified
mitochondrial insufficiency as a cell-intrinsic trigger that initiates the functional exhaustion of T cells.
At the molecular level, our findings indicate that mitochondrial dysfunction leads to redox stress,
which, in turn, hinders the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and
facilitates the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T
cells

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Universität Freiburg, Dissertation, 2024

Klassifikation und Themen

• Schlagwort: T-Lymphozyt ; Immunreaktion ; Cytologie

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2024
• Urheber: Mansilla, Ana Maria
• Beteiligte Personen und Organisationen: Kastenmüller, Wolfgang ; Rambold, Angelika ; Martin, Stefan F. ; Albert-Ludwigs-Universität Freiburg. Fakultät für Biologie

Weitere Informationen

• DOI: 10.6094/UNIFR/255889
• URN: urn:nbn:de:bsz:25-freidok-2558896
• Rechteinformation: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 01.08.2025, 07:42 MESZ