T cell homeostasis requires G protein-coupled receptor-mediated access to trophic signals that promote growth and inhibit chemotaxis.
Signals that regulate T cell homeostasis are not fully understood. G protein-coupled receptors (GPCR), such as the chemokine receptors, may affect homeostasis by direct signaling or by guiding T cell migration to distinct location-restricted signals. Here, we show that blockade of Galphai-associated GPCR signaling by treatment with pertussis toxin led to T cell atrophy and shortened life-span in T cell-replete hosts and prevented T cell homeostatic growth and proliferation in T cell-deficient hosts. In vitro, however, neither GPCR inhibition nor chemokine stimulation affected T cell atrophy, survival, or proliferation. These findings suggest that GPCR signals are not trophic stimuli, but instead may be required for migration to distinct trophic signals, such as IL-7 or self-peptide/MHC. Surprisingly, while chemokines did not affect atrophy, atrophic T cells displayed increased chemokine-induced chemotaxis that was prevented by IL-7 and submitogenic anti-CD3 antibody treatment. This increase in migration was associated with increased levels of GTP-bound Rac and the ability to remodel actin. These data suggest a novel mechanism of T cell homeostasis wherein GPCR may promote T cell migration to distinct location-restricted homeostatic trophic cues for T cell survival and growth. Homeostatic trophic signals, in turn, may suppress chemokine sensitivity and cytoskeletal remodeling, to inhibit further migration.
Cinalli
Ryan M
RM
Abramson Family Cancer Research Institute, Departments of Cancer Biology and Medicine, University of Pennsylvania, Philadelphia, USA.
Herman
Catherine E
CE
Lew
Brian O
BO
Wieman
Heather L
HL
Thompson
Craig B
CB
Rathmell
Jeffrey C
JC
D000199:Actins / Q000276:immunology / Q000378:metabolism; D019264:Adoptive Transfer; D000818:Animals; D001284:Atrophy / Q000276:immunology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002633:Chemotaxis / Q000276:immunology*; D003599:Cytoskeleton / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006133:Growth Substances / Q000276:immunology*; D006706:Homeostasis / Q000276:immunology*; D015851:Interleukin-7 / Q000276:immunology / Q000378:metabolism; D008221:Lymphoid Tissue / Q000473:pathology; D051379:Mice; D037342:Pertussis Toxin / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D018121:Receptors, Cytokine / Q000276:immunology; D043562:Receptors, G-Protein-Coupled / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D000199:Actins; D006133:Growth Substances; D015851:Interleukin-7; D011948:Receptors, Antigen, T-Cell; D018121:Receptors, Cytokine; D043562:Receptors, G-Protein-Coupled; D037342:Pertussis Toxin
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