TY - JOUR
T1 - Kidney Failure Associates With T Cell Exhaustion and Imbalanced Follicular Helper T Cells
AU - Hartzell, Susan
AU - Bin, Sofia
AU - Cantarelli, Chiara
AU - Haverly, Meredith
AU - Manrique, Joaquin
AU - Angeletti, Andrea
AU - Manna, Gaetano La
AU - Murphy, Barbara
AU - Zhang, Weijia
AU - Levitsky, Josh
AU - Gallon, Lorenzo
AU - Yu, Samuel Mon Wei
AU - Cravedi, Paolo
N1 - Funding Information:
This study has been supported by an investigator-initiated grant from the Renal Research Institute. We want to particularly acknowledge the patients and the Biobank Navarrabiomed (PT17/0015/0007) integrated in the Spanish National Biobanks Network for their collaboration.
Funding Information:
Funding. This study has been supported by an investigator-initiated grant from the Renal Research Institute. We want to particularly acknowledge the patients and the Biobank Navarrabiomed (PT17/0015/0007) integrated in the Spanish National Biobanks Network for their collaboration.
Publisher Copyright:
© Copyright © 2020 Hartzell, Bin, Cantarelli, Haverly, Manrique, Angeletti, Manna, Murphy, Zhang, Levitsky, Gallon, Yu and Cravedi.
PY - 2020/9/29
Y1 - 2020/9/29
N2 - Individuals with kidney failure are at increased risk of cardiovascular events, as well as infections and malignancies, but the associated immunological abnormalities are unclear. We hypothesized that the uremic milieu triggers a chronic inflammatory state that, while accelerating atherosclerosis, promotes T cell exhaustion, impairing effective clearance of pathogens and tumor cells. Clinical and demographic data were collected from 78 patients with chronic kidney disease (CKD) (n = 42) or end-stage kidney disease (ESKD) (n = 36) and from 18 healthy controls (HC). Serum cytokines were analyzed by Luminex. Immunophenotype of T cells was performed by flow cytometry on peripheral blood mononuclear cells. ESKD patients had significantly higher serum levels of IFN-γ, TNF-α, sCD40L, GM-CSF, IL-4, IL-8, MCP-1, and MIP-1β than CKD and HC. After mitogen stimulation, both CD4+ and CD8+ T cells in ESKD group demonstrated a pro-inflammatory phenotype with increased IFN-γ and TNF-α, whereas both CKD and ESKD patients had higher IL-2 levels. CKD and ESKD were associated with increased frequency of exhausted CD4+ T cells (CD4+KLRG1+PD1+CD57−) and CD8+ T cells (CD8+KLRG1+PD1+CD57−), as well as anergic CD4+ T cells (CD4+KLRG1−PD1+CD57−) and CD8+ T cells (CD8+KLRG1−PD1+CD57−). Although total percentage of follicular helper T cell (TFH) was similar amongst groups, ESKD had reduced frequency of TFH1 (CCR6−CXCR3+CXCR5+PD1+CD4+CD8−), but increased TFH2 (CCR6−CXCR3−CXCR5+PD1+CD4+CD8−), and plasmablasts (CD3−CD56−CD19+CD27highCD38highCD138−). In conclusion, kidney failure is associated with pro-inflammatory markers, exhausted T cell phenotype, and upregulated TFH2, especially in ESKD. These immunological changes may account, at least in part, for the increased cardiovascular risk in these patients and their susceptibility to infections and malignancies.
AB - Individuals with kidney failure are at increased risk of cardiovascular events, as well as infections and malignancies, but the associated immunological abnormalities are unclear. We hypothesized that the uremic milieu triggers a chronic inflammatory state that, while accelerating atherosclerosis, promotes T cell exhaustion, impairing effective clearance of pathogens and tumor cells. Clinical and demographic data were collected from 78 patients with chronic kidney disease (CKD) (n = 42) or end-stage kidney disease (ESKD) (n = 36) and from 18 healthy controls (HC). Serum cytokines were analyzed by Luminex. Immunophenotype of T cells was performed by flow cytometry on peripheral blood mononuclear cells. ESKD patients had significantly higher serum levels of IFN-γ, TNF-α, sCD40L, GM-CSF, IL-4, IL-8, MCP-1, and MIP-1β than CKD and HC. After mitogen stimulation, both CD4+ and CD8+ T cells in ESKD group demonstrated a pro-inflammatory phenotype with increased IFN-γ and TNF-α, whereas both CKD and ESKD patients had higher IL-2 levels. CKD and ESKD were associated with increased frequency of exhausted CD4+ T cells (CD4+KLRG1+PD1+CD57−) and CD8+ T cells (CD8+KLRG1+PD1+CD57−), as well as anergic CD4+ T cells (CD4+KLRG1−PD1+CD57−) and CD8+ T cells (CD8+KLRG1−PD1+CD57−). Although total percentage of follicular helper T cell (TFH) was similar amongst groups, ESKD had reduced frequency of TFH1 (CCR6−CXCR3+CXCR5+PD1+CD4+CD8−), but increased TFH2 (CCR6−CXCR3−CXCR5+PD1+CD4+CD8−), and plasmablasts (CD3−CD56−CD19+CD27highCD38highCD138−). In conclusion, kidney failure is associated with pro-inflammatory markers, exhausted T cell phenotype, and upregulated TFH2, especially in ESKD. These immunological changes may account, at least in part, for the increased cardiovascular risk in these patients and their susceptibility to infections and malignancies.
KW - ESKD
KW - T cell
KW - dialysis (ESKD)
KW - exhaustion
KW - immune phenotype
KW - treg
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U2 - 10.3389/fimmu.2020.583702
DO - 10.3389/fimmu.2020.583702
M3 - Article
C2 - 33117396
AN - SCOPUS:85092532984
VL - 11
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
M1 - 583702
ER -