Heterogeneity of HBV-specific CD8+ T cells and CD56 dim NK cells and their impact on immune failure in chronic HBV infection

Abstract: Virus-specific CD8+ T cells and natural killer (NK) cells are crucial for hepatitis B virus (HBV) clearance but show an altered phenotype and impaired functionality in chronically HBV-infected (cHBV) patients. In this thesis, we aimed at a comprehensive subset characterization of HBV-specific CD8+ T cells and NK cells to dissect the contribution of phenotypically and functionally distinct subpopulations to the immune failure in cHBV infection and to identify new potential targets for immunotherapeutic approaches.
Enrichment of circulating HBV-specific CD8+ T cells in cHBV patients revealed that less differentiated memory-like CD127+PD1+ subsets predominate in cHBV infection and co-exist with a minor proportion of more severely exhausted CD127-PD1+ subpopulations. Importantly, antigen specificity clearly impacted subset distribution and thus the phenotype of core18- versus polymerase455-specific CD8+ T cells. More precisely, core18-specific CD8+ T cells showed a higher porportion of memory-like T cells and thus a decreased expression of exhaustion markers KLRG1 and Eomes. In line with this, core18-specific CD8+ T cells displayed a surperior expansion capacity compared to polymerase455-specific CD8+ T-cell populations. This was not primarily due to a differential proliferative capacity but rather to different survival characteristics reflected by an increased expression of BCL2 in core18- compared to polymerase455-specific CD8+ T cells.
In addition to CD8+ T-cell heterogeneity, subsets of circulating CD56dim NK cells were identified by analysis of FcεRIγ expression and revealed an increased prevalence and frequency of adaptive FcεRIγ- CD56dim NK cells in cHBV patients in comparison to healthy donors (HD). Indeed, we phenotypically and functionally confirmed the adaptive profile of the FcεRIγ- subset showing reduced cytokine responsiveness and enhanced CD16-mediated effector function. The adaptive characteristics were conserved in cHBV patients compared to HD, suggesting high stability of the FcεRIγ- CD56dim NK-cell subpopulation. The frequency of adaptive FcεRIγ- CD56dim NK cells largely correlated with the phenotype and function of the overall CD56dim NK population, pointing to a role of adaptive FcεRIγ- CD56dim NK-cell subset abundance to the NK-cell profile in cHBV patients.
In sum, our results revealed differential exhaustion profiles of core18- versus polymerase455-specific CD8+ T cells, suggesting that immunotherapeutic targeting of HBV-specific CD8+ T-cell responses may require different strategies depending on the specificity of the targeted population. Additionally, due to their increased potential for CD16-mediated effector functions in cHBV patients, antibody-based immunotherapeutic approaches may require consideration of present adaptive FcεRIγ- CD56dim NK-cell populations. Importantly, both studies revealed novel insights that might be relevant for the design of future immunotherapies to cure cHBV patients

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Universität Freiburg, Dissertation, 2018

Klassifikation und Themen

• Schlagwort: Hepatitis-B-Virus

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2018
• Urheber: Schuch, Anita
• Beteiligte Personen und Organisationen: Thimme, Robert ; Albert-Ludwigs-Universität Freiburg. Fakultät für Biologie

Weitere Informationen

• DOI: 10.6094/UNIFR/15980
• URN: urn:nbn:de:bsz:25-freidok-159802
• Rechteinformation: Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 25.03.2025, 13:49 MEZ