CD57 identifies T cells with functional senescence before terminal differentiation and relative telomere shortening in patients with activated PI3 kinase delta syndrome

Abstract

Premature T-cell immunosenescence with CD57 CD8 T-cell accumulation has been linked to immunodeficiency and autoimmunity in primary immunodeficiencies including activated PI3 kinase delta syndrome (APDS). To address whether CD57 marks the typical senescent T-cell population seen in adult individuals or identifies a distinct population in APDS, we compared CD57 CD8 T cells from mostly pediatric APDS patients to those of healthy adults with similarly prominent senescent T cells. CD57 CD8 T cells from APDS patients were less differentiated with more CD27 CD28 effector memory T cells showing increased PD1 and Eomesodermin expression. In addition, transition of naïve to CD57 CD8 T cells was not associated with the characteristic telomere shortening. Nevertheless, they showed the increased interferon-gamma secretion, enhanced degranulation and reduced in vitro proliferation typical of senescent CD57 CD8 T cells. Thus, hyperactive PI3 kinase signaling favors premature accumulation of a CD57 CD8 T-cell population, which shows most functional features of typical senescent T cells, but is different in terms of differentiation and relative telomere shortening. Initial observations indicate that this specific differentiation state may offer the opportunity to revert premature T-cell immunosenescence and its potential contribution to inflammation and immunodeficiency in APDS.

CD8+ T‐cell senescence and skewed lymphocyte subsets in young Dyskeratosis Congenita patients with PARN and DKC1 mutations

“…Both patients in our study had short telomeres, consistent with previous reports 11,24,34 . Because the telomere length is highly variable according to race, age, and disease state, the cell surface marker CD57 is routinely used to identify terminally differentiated, senescent cells with reduced proliferative capacity and altered functional properties 22 . The expression of CD57 was dramatically elevated in CD4 and CD8 T cells in both patients in our study.…”

“…The expression of CD57 in T cells was also analyzed by flow cytometry 22 . Isolated PBMCs were incubated with anti‐human CD4 (PE‐Cy7), anti‐human CD8 (BV421), and anti‐human CD57 (FITC) for 30 minutes on ice.…”

Activated PI3Kδ breaches multiple B cell tolerance checkpoints and causes autoantibody production

“…Interestingly, ∼40% of PIK3CD GOF patients also develop clinically relevant autoimmune disease, including autoimmune cytopenias, glomerulonephritis, and autoimmune thyroiditis (Coulter et al, 2017;Lucas et al, 2014;Maccari et al, 2018). Several recent studies have explored the pathogenesis of the immunodeficiency in these patients (Avery et al, 2018;Bier et al, 2019;Cannons et al, 2018;Cura Daball et al, 2018;Edwards et al, 2019;Preite et al, 2018;Preite et al, 2019;Ruiz-García et al, 2018;Stark et al, 2018;Wentink et al, 2017;Wentink et al, 2018;Wray-Dutra et al, 2018). These studies have revealed defects in B cells and CD4 + T cells, thereby elucidating mechanisms for poor antibody responses and susceptibility to respiratory infections, and altered natural killer and CD8 + T cell function, which provide an explanation for the viral susceptibility and possibly malignancy.…”

Higher Incidence of B Cell Malignancies in Primary Immunodeficiencies: A Combination of Intrinsic Genomic Instability and Exocytosis Defects at the Immunological Synapse

“…It is produced upon phosphorylation of PIP2 by the phosphoinositide 3-kinases (PI3K), especially PI3Kδ. Interestingly, mutations in the subunits of PI3K also translate into multiple PID associated with decreased NK cell cytotoxicity ( 196 , 197 ) and CD8 + T cell proliferation ( 198 ). In addition to DGK-α, PIP3 also recruits DOCK2, which is needed to drive a Rac1/WAVE2-dependent actin polymerization at the pSMAC ( 199 , 200 ).…”