TY - JOUR
T1 - Context-Dependent Role for T-bet in T Follicular Helper Differentiation and Germinal Center Function following Viral Infection
AU - Sheikh, Amania A.
AU - Cooper, Lucy
AU - Feng, Meiqi
AU - Souza-Fonseca-Guimaraes, Fernando
AU - Lafouresse, Fanny
AU - Duckworth, Brigette C.
AU - Huntington, Nicholas D.
AU - Moon, James J.
AU - Pellegrini, Marc
AU - Nutt, Stephen L.
AU - Belz, Gabrielle T.
AU - Good-Jacobson, Kim L.
AU - Groom, Joanna R.
PY - 2019/8/13
Y1 - 2019/8/13
N2 - Following infection, inflammatory cues upregulate core transcriptional programs to establish pathogen-specific protection. In viral infections, T follicular helper (TFH) cells express the prototypical T helper 1 transcription factor T-bet. Several studies have demonstrated essential but conflicting roles for T-bet in TFH biology. Understanding the basis of this controversy is crucial, as modulation of T-bet expression instructs TFH differentiation and ultimately protective antibody responses. Comparing influenza and LCMV viral infections, we demonstrate that the role of T-bet is contingent on the environmental setting of TFH differentiation, IL-2 signaling, and T cell competition. Furthermore, we demonstrate that T-bet expression by either TFH or GC B cells independently drives antibody isotype class switching. Specifically, T cell-specific loss of T-bet promotes IgG1, whereas B cell-specific loss of T-bet inhibits IgG2a/c switching. Combined, this work highlights that the context-dependent induction of T-bet instructs the development of protective, neutralizing antibodies following viral infection or vaccination. Shiekh et al. show that, in influenza and LCMV infections, the role of the transcription factor T-bet in TFH differentiation is contingent on environmental cues, IL-2 signaling, and T cell competition. Cell-specific T-bet expression independently drives antibody isotype class switching. Therefore T-bet instructs immune protection in a context-dependent manner.
AB - Following infection, inflammatory cues upregulate core transcriptional programs to establish pathogen-specific protection. In viral infections, T follicular helper (TFH) cells express the prototypical T helper 1 transcription factor T-bet. Several studies have demonstrated essential but conflicting roles for T-bet in TFH biology. Understanding the basis of this controversy is crucial, as modulation of T-bet expression instructs TFH differentiation and ultimately protective antibody responses. Comparing influenza and LCMV viral infections, we demonstrate that the role of T-bet is contingent on the environmental setting of TFH differentiation, IL-2 signaling, and T cell competition. Furthermore, we demonstrate that T-bet expression by either TFH or GC B cells independently drives antibody isotype class switching. Specifically, T cell-specific loss of T-bet promotes IgG1, whereas B cell-specific loss of T-bet inhibits IgG2a/c switching. Combined, this work highlights that the context-dependent induction of T-bet instructs the development of protective, neutralizing antibodies following viral infection or vaccination. Shiekh et al. show that, in influenza and LCMV infections, the role of the transcription factor T-bet in TFH differentiation is contingent on environmental cues, IL-2 signaling, and T cell competition. Cell-specific T-bet expression independently drives antibody isotype class switching. Therefore T-bet instructs immune protection in a context-dependent manner.
KW - germinal center
KW - influenza
KW - isotope switching
KW - T cell differentiation
KW - T follicular helper
KW - T helper 1
KW - T-bet
KW - transcriptional regulation
KW - viral infection
UR - http://www.scopus.com/inward/record.url?scp=85070199715&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2019.07.034
DO - 10.1016/j.celrep.2019.07.034
M3 - Article
AN - SCOPUS:85070199715
VL - 28
SP - 1758
EP - 1772
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 7
ER -