Context-dependent role for T-bet in T follicular helper differentiation and germinal center function following viral infection
Sheikh, AA; Cooper, L; Feng, M; Souza-Fonseca-Guimaraes, F; Lafouresse, F; Duckworth, BC; Huntington, ND; Moon, JJ; Pellegrini, M; Nutt, SL; Belz, GT; Good-Jacobson, KL; Groom, JR
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.
Immunology; Infectious Diseases and Immune Defence