Transcriptional Pattern Analysis of Virus-Specific CD8+ T Cells in Hepatitis C Infection: Increased Expression of TOX and Eomesodermin During and After Persistent Antigen Recognition
Standard
Transcriptional Pattern Analysis of Virus-Specific CD8+ T Cells in Hepatitis C Infection: Increased Expression of TOX and Eomesodermin During and After Persistent Antigen Recognition. / Wildner, Nils H; Walker, Andreas; Brauneck, Franziska; Ditt, Vanessa; Peine, Sven; Huber, Samuel; Haag, Friedrich; Beisel, Claudia; Timm, Joerg; Schulze Zur Wiesch, Julian.
In: FRONT IMMUNOL, Vol. 13, 886646, 2022.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Transcriptional Pattern Analysis of Virus-Specific CD8+ T Cells in Hepatitis C Infection: Increased Expression of TOX and Eomesodermin During and After Persistent Antigen Recognition
AU - Wildner, Nils H
AU - Walker, Andreas
AU - Brauneck, Franziska
AU - Ditt, Vanessa
AU - Peine, Sven
AU - Huber, Samuel
AU - Haag, Friedrich
AU - Beisel, Claudia
AU - Timm, Joerg
AU - Schulze Zur Wiesch, Julian
N1 - Copyright © 2022 Wildner, Walker, Brauneck, Ditt, Peine, Huber, Haag, Beisel, Timm and Schulze zur Wiesch.
PY - 2022
Y1 - 2022
N2 - Thymocyte selection-associated high mobility group box (TOX) has been described to be a key regulator in the formation of CD8+ T cell exhaustion. Hepatitis C virus (HCV) infection with different lengths of antigen exposure in acute, chronic, and after resolution of HCV infection is the ideal immunological model to study the expression of TOX in HCV-specific CD8+ T cells with different exposure to antigen. HCV-specific CD8+ T cells from 35 HLA-A*01:01, HLA-A*02:01, and HLA-A*24:02 positive patients were analyzed with a 16-color FACS-panel evaluating the surface expression of lineage markers (CD3, CD8), ectoenzymes (CD39, CD73), markers of differentiation (CD45RO, CCR7, CD127), and markers of exhaustion and activation (TIGIT, PD-1, KLRG1, CD226) and transcription factors (TOX, Eomesodermin, T-bet). Here, we defined on-target T cells as T cells against epitopes without escape mutations and off-target T cells as those against a "historical" antigen mutated in the autologous sequence. TOX+HCV-specific CD8+ T cells from patients with chronic HCV and on-target T cells displayed co-expression of Eomesodermin and were associated with the formation of terminally exhausted CD127-PD1hi, CD39hi, CD73low CD8+ T cells. In contrast, TOX+HCV-specific CD8+ T cells in patients with off-target T cells represented a progenitor memory Tex phenotype characterized by CD127hi expression and a CD39low and CD73hi phenotype. TOX+HCV-specified CD8+ T cells in patients with a sustained virologic response were characterized by a memory phenotype (CD127+, CD73hi) and co-expression of immune checkpoints and Eomesodermin, indicating a key structure in priming of HCV-specific CD8+ T cells in the chronic stage, which persisted as a residual after therapy. Overall, the occurrence of TOX+HCV-specific CD8+ T cells was revealed at each disease stage, which impacted the development of progenitor Tex, intermediate Tex, and terminally exhausted T cell through an individual molecular footprint. In sum, TOX is induced early during acute infection but is modulated by changes in viral sequence and antigen recognition. In the case of antigen persistence, the interaction with Eomesodermin leads to the formation of terminally exhausted virus-specific CD8+ T cells, and there was a direct correlation of the co-expression of TOX and Eomes and terminally exhausted phenotype of virus-specific CD8+ T cells.
AB - Thymocyte selection-associated high mobility group box (TOX) has been described to be a key regulator in the formation of CD8+ T cell exhaustion. Hepatitis C virus (HCV) infection with different lengths of antigen exposure in acute, chronic, and after resolution of HCV infection is the ideal immunological model to study the expression of TOX in HCV-specific CD8+ T cells with different exposure to antigen. HCV-specific CD8+ T cells from 35 HLA-A*01:01, HLA-A*02:01, and HLA-A*24:02 positive patients were analyzed with a 16-color FACS-panel evaluating the surface expression of lineage markers (CD3, CD8), ectoenzymes (CD39, CD73), markers of differentiation (CD45RO, CCR7, CD127), and markers of exhaustion and activation (TIGIT, PD-1, KLRG1, CD226) and transcription factors (TOX, Eomesodermin, T-bet). Here, we defined on-target T cells as T cells against epitopes without escape mutations and off-target T cells as those against a "historical" antigen mutated in the autologous sequence. TOX+HCV-specific CD8+ T cells from patients with chronic HCV and on-target T cells displayed co-expression of Eomesodermin and were associated with the formation of terminally exhausted CD127-PD1hi, CD39hi, CD73low CD8+ T cells. In contrast, TOX+HCV-specific CD8+ T cells in patients with off-target T cells represented a progenitor memory Tex phenotype characterized by CD127hi expression and a CD39low and CD73hi phenotype. TOX+HCV-specified CD8+ T cells in patients with a sustained virologic response were characterized by a memory phenotype (CD127+, CD73hi) and co-expression of immune checkpoints and Eomesodermin, indicating a key structure in priming of HCV-specific CD8+ T cells in the chronic stage, which persisted as a residual after therapy. Overall, the occurrence of TOX+HCV-specific CD8+ T cells was revealed at each disease stage, which impacted the development of progenitor Tex, intermediate Tex, and terminally exhausted T cell through an individual molecular footprint. In sum, TOX is induced early during acute infection but is modulated by changes in viral sequence and antigen recognition. In the case of antigen persistence, the interaction with Eomesodermin leads to the formation of terminally exhausted virus-specific CD8+ T cells, and there was a direct correlation of the co-expression of TOX and Eomes and terminally exhausted phenotype of virus-specific CD8+ T cells.
KW - CD8-Positive T-Lymphocytes
KW - HLA-A Antigens/metabolism
KW - Hepacivirus
KW - Hepatitis C/immunology
KW - High Mobility Group Proteins/genetics
KW - Humans
KW - Lymphocyte Activation
KW - T-Box Domain Proteins/genetics
U2 - 10.3389/fimmu.2022.886646
DO - 10.3389/fimmu.2022.886646
M3 - SCORING: Journal article
C2 - 35734162
VL - 13
JO - FRONT IMMUNOL
JF - FRONT IMMUNOL
SN - 1664-3224
M1 - 886646
ER -