Pinpointing IL-4-independent acquisition and IL-4-influenced maintenance of Th2 activity by CD4 T cells.
Naive CD4 T cells develop Th2 activity early in primary responses to alum-precipitated proteins by producing IL-4 mRNA and inducing B cells to produce gamma1 and epsilon switch transcripts. Both IL-4-dependent and IL-4-independent pathways for IL-4 induction are recognized, but their relative contribution to the different phases of primary Th2 responses in vivo is uncertain. We show the primary induction of IL-4 synthesis in lymph nodes responding to alum-precipitated protein is overwhelmingly in antigen-specific CD4 T cells and is unimpaired in IL-4Ralpha(-/-) mice, which can produce but do not respond to IL-4 and IL-13. Ig class-switching in extra-follicular responses, reflecting Th2 activity, is also unimpaired in these mice. By contrast, 7 days after immunization--when T cells are selecting B cells in germinal centers and T cell priming has occurred--non-responsiveness to IL-4 is associated with smaller germinal centers, increased levels of T-bet and gamma2a switch transcripts and reduced gamma1 and epsilon transcripts. These data indicate that Th2 characteristics acquired during T cell priming and the initial CD4 T cell interaction with B cells are largely IL-4-independent, whereas IL-4 production induced during priming has a significant role in maintaining the Th2 phenotype as T cells select B cells in germinal centers.
The Medical Research Council Centre for Immune Regulation, University of Birmingham, Birmingham, GB.
Adam F
AF
Cunningham
The Medical Research Council Centre for Immune Regulation, University of Birmingham, Birmingham, GB.
Karine
K
Serre
The Medical Research Council Centre for Immune Regulation, University of Birmingham, Birmingham, GB.
Kai-Michael
KM
Toellner
The Medical Research Council Centre for Immune Regulation, University of Birmingham, Birmingham, GB.
Mahmood
M
Khan
Department of Immunology, University of Strathclyde, Glasgow, GB.
James
J
Alexander
Medical Research Council Unit Immunology in Infectious Diseases, Division of Immunology, University of Cape Town, Groote Schuur Hospital, Cape Town, South Africa.
Frank
F
Brombacher
The Medical Research Council Centre for Immune Regulation, University of Birmingham, Birmingham, GB.
Ian C M
ICM
MacLennan
D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D018858:Germinal Center / Q000276:immunology; D018793:Interleukin-13 / Q000502:physiology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000502:physiology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D019948:Receptors, Interleukin-4 / Q000235:genetics; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
D018793:Interleukin-13; D019948:Receptors, Interleukin-4; D015847:Interleukin-4; D010047:Ovalbumin