Prolonged Interleukin-2Rα Expression on Virus-Specific CD8+ T Cells Favors Terminal-Effector Differentiation In Vivo

Abstract

CD25, the high-affinity interleukin-2 (IL-2) receptor alpha chain, is rapidly upregulated by antigen-specific CD8(+) T cells after T cell receptor stimulation. Here, we demonstrate that during an acute viral infection, CD25 expression is quite dynamic-after initial upregulation, a subset of virus-specific T cells sustains CD25 expression longer than the rest. At this time when there is distinct heterogeneity in CD25 expression, examination of the in vivo fate of effector cells revealed that CD25(lo) cells, which are relatively less sensitive to IL-2, preferentially upregulate CD127 and CD62L and give rise to functional long-lived memory cells. In contrast, CD25(hi) cells perceiving prolonged IL-2 signals proliferate more rapidly, are prone to apoptosis, exhibit a more pronounced effector phenotype, and appear to be terminally differentiated. Consistent with this, sustained IL-2 receptor signaling during expansion drove terminal-effector differentiation. These data support the hypothesis that prolonged IL-2 signals during priming promote terminal-effector differentiation.

Differential Impact of CD27 and 4-1BB Costimulation on Effector and Memory CD8 T Cell Generation following Peptide Immunization

“…6A, 6B). In contrast, prolonged expression of CD25 was a more informative predictor of cells that differentiate into short-term memory cells, thus corroborating previous findings obtained in the acute lymphocytic choriomeningitis virus infection model (7). Additionally, our data highlight increased expression of CD71 and Gp49b as potentially useful in identifying short-term memory precursor cells.…”

“…4E). Prolonged expression of CD25 on a subset of activated CD8 T cells during acute viral infection was shown to mark a population of cells with enhanced effector function and inability to mature into functional long-lived memory cells (7). Therefore, our data identify CD27 as a key driver of sustained CD25 expression on activated CD8 T cells.…”

“…Kalia et al (7) reported that, within 3.5 d of infection with lymphocytic choriomeningitis virus, prolonged expression of IL-2Ra (CD25) marks a population of Ag-specific CD8 T cells that is enriched in short-lived effector cells (SLECs). Compared with cells that expressed low amounts of CD25, these cells proliferated more rapidly, exhibited a more pronounced effector phenotype, and were more prone to apoptosis (7). Further support for a role for IL-2 in regulating effector cell differentiation and determining memory T cell fate was provided by studies of CD25-deficient T cells.…”

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

“…Highly specialized regulatory T cells (Tregs) are dependent on IL-2 for survival and express large numbers of IL-2Ra, but they are unable to produce IL-2. These cells are thought to mediate active but selective immune suppression and are critical in the maintenance of self-tolerance (Rouse and Suvas 2004;Burchill et al 2007;Josefowicz and Rudensky 2009;Pipkin et al 2010;Kalia et al 2010). …”

EFFECTS OF γс-CYTOKINES (IL-2, IL-7 AND IL-15) UPON IN VITRO MATURATION AND DIFFERENTIATION OF CD4⁺CD45RО⁺/CD8⁺CD45RО⁺ T CELLS

“…Ряд проведенных исследований убедитель-но доказали, что интенсивное и постоянное воздействие IL-2 способствует образованию CD8 + T EMRA [22]. Группой зарубежных авторов было установлено, что CD8 + Т-клетки, повторно экспрессирующие молекулу CD45RA, дифферен-цируются из T CM -CD8 + CD45RA -CCR7 + в при-сутствии IL-7 и IL-15 в отсутствие антигенного стимула, вероятно, за счет гомеостатической про-лиферации CD45RA -CCR7 + прекурсоров, в свя-зи с повышенной гибелью CD45R + CCR7 -кле-ток и их низкой способностью к рециркуляции в организме [18].…”