Abstract
Poorly functional effector CD8 T cells are generated in some pathological situations, including responses to weakly antigenic tumors. To identify the molecular bases for such defective differentiation, we monitored gene expression in naive monoclonal CD8 T cells during responses to TCR ligands of different affinity. We further evaluated whether responses to weak Ags may be improved by addition of cytokines. Transient gene expression was observed for a cluster of genes in response to the weak TCR agonist. Strikingly, gene expression was stabilized by low dose IL-2. This IL-2-sustained gene cluster encoded notably transcripts for CD25, cytolytic effector molecules (granzyme B) and TNF-R family costimulatory molecules (glucocorticoid-induced TNF-R (GITR), OX40, and 4-1BB). IL-2-enhanced surface expression or function was also demonstrated in vivo for these genes. A constitutive active form of STAT5 mimicked the IL-2 effect by sustaining transcripts for the same gene cluster. Consistent with this, under conditions of low avidity TCR engagement and IL-2 treatment, endogenous STAT5 binding to 4-1BB and granzyme B promoters was demonstrated by chromatin immunoprecipitation. This study highlights those genes for which IL-2, via STAT5 activation, acts as a stabilizer of gene regulation initiated by TCR signals, contributing to the development of a complete CD8 T cell effector program.
Highlights
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We addressed the question of the influence of strength of TCR signal on the development of a functional program in naive alloreactive CD8 T cells in a 2- to 4-day window after antigenic stimulation
CDNA microarray analysis revealed an important feature of IL-2 on primary activated CD8 T cells, namely a costimulatory effect on sustained regulation of Ag-induced gene expression for a subset of genes that included CTL effector molecules and TNF-R family members (GITR, 4-1BB, and OX40) thought to be important for T cell costimulation
Summary
GVHR, graft-vs-host reactions; GzmB, granzyme B; Lt-␣, lymphotoxin ␣; ChIP, chromatin immunoprecipitation. For naive CD8 T cells a more complex hierarchy was observed with production of IL-2 being a limiting factor [7, 8]. A kinetic analysis of gene expression patterns after Ag stimulation revealed that two main signaling pathways emanating from the TCR and the high affinity IL-2R contribute, respectively, to the initiation and to the stabilization of the CD8 T cell effector gene expression program. Endogenous STAT5 binding to 4-1BB, CD25, granzyme B (GzmB), and lymphotoxin-␣ (Lt-␣) promoter regions was detected by chromatin immunoprecipitation (ChIP) in conditions of weak TCR engagement in the presence of IL-2
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