STAT5-mediated signals sustain a TCR-initiated gene expression program toward differentiation of CD8 T cell effectors.
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.
Verdeil
Grégory
G
Centre d'Immunologie de Marseille-Luminy, Centre National de la Recherche Scientifique-Institut National de la Santé et de la Recherche Médicale-Université de la Méditerranée, Marseille, France.
Puthier
Denis
D
Nguyen
Catherine
C
Schmitt-Verhulst
Anne-Marie
AM
Auphan-Anezin
Nathalie
N
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation; D004247:DNA / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D005816:Genetic Complementation Test; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D018448:Models, Immunological; D020411:Oligonucleotide Array Sequence Analysis; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D004247:DNA