The strength of T cell stimulation determines IL-7 responsiveness, secondary expansion, and lineage commitment of primed human CD4+IL-7Rhi T cells.
Mouse memory T cell precursors express IL-7 receptor-alpha (IL-7R), proliferate with homeostatic cytokines and undergo secondary expansions with antigen. Here, we analyzed how the strength of antigenic stimulation regulates IL-7R expression, cytokine responsiveness and expansion potential of DC-primed human CD4(+ )T cells. IL-7R expression on proliferating T cells was highest at intermediate strength of stimulation, and purified CCR7(+)IL-7R(hi) and CCR7(-)IL-7R(lo) subsets had characteristics of memory and effector cells, respectively. However, CCR7(+)IL-7R(hi) cells generated under different priming conditions had strikingly different properties. Thus, increasing strength of stimulation promoted IL-7 responsiveness that correlated with reduced phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression and enhanced s6 kinase activation, suggesting a tunable IL-7R coupling to PI3 kinase-dependent signaling pathways. Furthermore, functional and gene expression analysis revealed that intermediate-stimulated CCR7(+)IL-7R(hi) cells were similar to non-polarized central memory cells with high expansion potential. Conversely, high-stimulated CCR7(+)IL-7R(hi) cells shared characteristics with circulating pre-Th1 cells and differentiated spontaneously to Th1 effector cells. These results show that the strength of stimulation determines properties of activated IL-7R(hi) T cells, and suggest that memory T cell subsets could be derived from CCR7(+) precursors that received different strengths of stimulation.
Lozza
Laura
L
Institute for Research in Biomedicine, Bellinzona, Switzerland.
Rivino
Laura
L
Guarda
Greta
G
Jarrossay
David
D
Rinaldi
Andrea
A
Bertoni
Francesco
F
Sallusto
Federica
F
Lanzavecchia
Antonio
A
Geginat
Jens
J
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019070:Cell Lineage; D002478:Cells, Cultured; D016207:Cytokines; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007156:Immunologic Memory; D015851:Interleukin-7 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D054400:Receptors, CCR7 / Q000276:immunology; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
C515370:CCR7 protein, human; D016207:Cytokines; C508605:IL7 protein, human; D015851:Interleukin-7; D054400:Receptors, CCR7; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain