Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions.
Current T cell differentiation models invoke separate T helper 2 (Th2) and Th1 cell lineages governed by the lineage-specifying transcription factors GATA-3 and T-bet. However, knowledge on the plasticity of Th2 cell lineage commitment is limited. Here we show that infection with Th1 cell-promoting lymphocytic choriomeningitis virus (LCMV) reprogrammed otherwise stably committed GATA-3(+) Th2 cells to adopt a GATA-3(+)T-bet(+) and interleukin-4(+)interferon-gamma(+) "Th2+1" phenotype that was maintained in vivo for months. Th2 cell reprogramming required T cell receptor stimulation, concerted type I and type II interferon and interleukin-12 signals, and T-bet. LCMV-triggered T-bet induction in adoptively transferred virus-specific Th2 cells was crucial to prevent viral persistence and fatal immunopathology. Thus, functional reprogramming of unfavorably differentiated Th2 cells may facilitate the establishment of protective immune responses. Stable coexpression of GATA-3 and T-bet provides a molecular concept for the long-term coexistence of Th2 and Th1 cell lineage characteristics in single memory T cells.
Hegazy
Ahmed N
AN
Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, 10117 Berlin, Germany.
Peine
Michael
M
Helmstetter
Caroline
C
Panse
Isabel
I
Fröhlich
Anja
A
Bergthaler
Andreas
A
Flatz
Lukas
L
Pinschewer
Daniel D
DD
Radbruch
Andreas
A
Löhning
Max
M
D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D016207:Cytokines / Q000276:immunology; D005434:Flow Cytometry; D050990:GATA3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020825:T-Box Domain Proteins / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D000098815:T-bet Transcription Factor
D016207:Cytokines; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma