Dysregulation of IL-15-mediated T-cell homeostasis in TGF-beta dominant-negative receptor transgenic mice.
T-cell subpopulations, defined by their expression of CD4, CD8, naive, and memory cell-surface markers, occupy distinct homeostatic compartments that are regulated primarily by cytokines. CD8+ memory T cells, as defined by CD44(hi) surface expression, are dependent on IL-15 as a positive regulator of their homeostatic maintenance. Manipulation of IL-15 signaling through gene aberration, overexpression, or receptor alterations has been shown to dramatically affect T-cell homeostasis, with overexpression leading to fatal leukemia. Here we show that TGF-beta is the critical negative regulator of murine CD8+ memory T-cell homeostasis with direct opposition to the positive effects of IL-15. This negative regulation is mediated, at least in part, by the ability of TGF-beta to modulate expression of the beta-chain of the IL-15 receptor, thus establishing a central axis between these 2 cytokines for homeostatic control of CD8+ memory T-cell populations. These data establish TGF-beta as a critical and dominant tumor-suppressor pathway opposing IL-15-mediated CD8+ T-cell expansion and potential malignant transformation.
Lucas
Philip J
PJ
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, CRC/3-3288, 10 Center Drive, Bethesda, MD 20892, USA. pjlucas@nih.gov
Kim
Seong-Jin
SJ
Mackall
Crystal L
CL
Telford
William G
WG
Chu
Yu-Waye
YW
Hakim
Frances T
FT
Gress
Ronald E
RE
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D005260:Female; D019672:Genes, T-Cell Receptor; D006706:Homeostasis; D007156:Immunologic Memory; D019409:Interleukin-15 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
C508025:Il15ra protein, mouse; D019409:Interleukin-15; D007376:Interleukin-2; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II