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

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.