Polar opposites: Erk direction of CD4 T cell subsets.
Effective immune responses depend upon appropriate T cell differentiation in accord with the nature of an infectious agent, and the contingency of differentiation depends minimally on TCR, coreceptor, and cytokine signals. In this reverse genetic study, we show that the MAPK Erk2 is not essential for T cell proliferation in the presence of optimum costimulation. Instead, it has opposite effects on T-bet and Gata3 expression and, hence, on Th1 and Th2 differentiation. Alternatively, in the presence of TGF-β, the Erk pathway suppresses a large program of gene expression, effectively limiting the differentiation of Foxp3(+) regulatory T cells. In the latter case, the mechanisms involved include suppression of Gata3 and Foxp3, induction of Tbx21, phosphorylation of Smad2,3, and possibly suppression of Socs2, a positive inducer of Stat5 signaling. Consequently, loss of Erk2 severely impeded Th1 differentiation while enhancing the development of Foxp3(+)-induced T regulatory cells. Selected profiles of gene expression under multiple conditions of T cell activation illustrate the opposing consequences of Erk pathway signaling.
University of California, San Diego, La Jolla, CA 92093-0377, USA.
Chiung-Fang
CF
Chang
Warren N
WN
D'Souza
Irene L
IL
Ch'en
Gilles
G
Pages
Jacques
J
Pouyssegur
Stephen M
SM
Hedrick
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000821:virology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology* / Q000821:virology; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology / Q000821:virology; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology / Q000821:virology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1