Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor.
As acute infections resolve, effector CD8(+) T cells differentiate into interleukin-7 receptor(lo) (IL-7R(lo)) short-lived effector cells (SLECs) and IL-7R(hi) memory precursor effector cells (MPECs) capable of generating long-lived memory CD8(+) T cells. By using another SLEC marker, KLRG1, we found that KLRG1(hi) effector cells began appearing early during infection and were committed to downregulating IL-7R. Unlike IL-7R(hi) MPECs, KLRG1(hi) IL-7R(lo) SLECs relied on IL-15, but IL-15 could not sustain their long-term maintenance or homeostatic turnover. The decision between SLEC and MPEC fates was regulated by the amount of inflammatory cytokines (i.e., IL-12) present during T cell priming. According to the amount of inflammation, a gradient of T-bet was created in which high T-bet expression induced SLECs and low expression promoted MPECs. These results elucidate a mechanism by which the innate immune system sets the relative amounts of a lineage-determining transcription factor in activated CD8(+) T cells and, correspondingly, regulates their memory cell potential.
Joshi
Nikhil S
NS
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Cui
Weiguo
W
Chandele
Anmol
A
Lee
Heung Kyu
HK
Urso
David R
DR
Hagman
James
J
Gapin
Laurent
L
Kaech
Susan M
SM
D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism*; D007156:Immunologic Memory; D007239:Infections / Q000276:immunology / Q000382:microbiology / Q000821:virology; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D019409:Interleukin-15 / Q000378:metabolism; D037181:Lectins, C-Type; D051379:Mice; D008817:Mice, Mutant Strains; D011971:Receptors, Immunologic / Q000032:analysis / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism*; D000098815:T-bet Transcription Factor
D015415:Biomarkers; D016207:Cytokines; D019409:Interleukin-15; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D020395:Receptors, Interleukin-7; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma