Constitutive activation of STAT5 supersedes the requirement for cytokine and TCR engagement of CD4+ T cells in steady-state homeostasis.
The transcription factor STAT5 is one of several signaling mediators activated via common gamma-chain cytokine receptors. As such, it plays an important role in lymphocyte survival and proliferation during normal homeostasis as well as under lymphopenic conditions. Transgenic mice expressing a constitutively activated form of STAT5b have been shown previously to contain increased numbers of peripheral CD4+CD25- T cells. To define the mechanism(s) for this occurrence, we have used adoptive transfer studies to examine the effects of STAT5 activity on steady-state CD4+ T cell homeostasis. We observed that constitutive STAT5 signaling induced 4- to 7-fold increased levels of basal steady-state proliferation, which was accompanied by a comparable increase in T cell recovery. Most strikingly, steady-state CD4 T cell proliferation occurred independently of both MHC class II and IL-15. These observations demonstrate that the STAT5-driven pathway is important to lymphocyte homeostasis and can supersede the need for both TCR engagement and cytokine stimulation. This suggests that the need for TCR stimulation to induce common gamma-chain cytokine receptor expression, and thus STAT5 activation, is a key factor in maintaining normal CD4+ T cell homeostasis.
Taylor
Devon K
DK
Department of Medicine, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104, USA.
Walsh
Patrick T
PT
LaRosa
David F
DF
Zhang
Jidong
J
Burchill
Matthew A
MA
Farrar
Michael A
MA
Turka
Laurence A
LA
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation; D016207:Cytokines / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D019409:Interleukin-15 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000502:physiology; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000637:transplantation
D016207:Cytokines; D000949:Histocompatibility Antigens Class II; C508025:Il15ra protein, mouse; D019409:Interleukin-15; D011948:Receptors, Antigen, T-Cell; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor