Protein Immunization Induces Memory CD4+ T Cells That Lack Th Lineage Commitment

Abstract

Acute viral infection generates lineage-committed Th1 and T follicular helper (Tfh) memory cells that recall their lineage-specific functions following secondary challenge with virus. However, the lineage commitment of effector and memory Th cells in vivo following protein vaccination is poorly understood. In this study, we analyzed effector and memory CD4+ T cell differentiation in mice (Mus musculus) following adjuvanted glycoprotein immunization compared with acute lymphocytic choriomeningitis virus infection. Glycoprotein immunization induced CXCR5− non-Tfh effector and memory CD4+ T cells that surprisingly had not undergone polarization toward any particular Th cell lineage but had undergone memory differentiation. However, upon challenge with virus, these Th lineage–nonpolarized memory CD4+ T cells were able to generate Th1 secondary effector cells, demonstrating their lineage plasticity. In addition, Tfh and memory Tfh cells were generated in response to protein immunization, and these cells differed from infection-induced Tfh cells by their lack of the transcription factor Tbet. Rechallenge experiments demonstrated that viral infection, but not protein immunization, during either the primary or secondary immune response, restricts the recall of Bcl6 expression and the generation of germinal center Tfh cells. Together, these data demonstrate that protein immunization generates a combination of nonpolarized memory cells that are highly plastic and memory Tfh cells that can undergo further Th1-like modulation during a secondary response to viral infection.

Generation of antigen-specific memory CD4 T cells by heterologous immunization enhances the magnitude of the germinal center response upon influenza infection

“…The lack of IFN-expressing cells in the GP(1 o ) group was expected, as we previously reported that adjuvanted rGP immunization induces expansion of a CXCR5-IFN-nonpolarized T helper cell population in lieu of highly IFN-expressing Th1 cells as seen following LCMV infection (60). Together, these data show that both adjuvanted rGP immunization and LCMV infection induced I-A b :gp66-77 tetramer+ memory CD4+ Tfh and non-Tfh cells.…”

“…When we analyzed for IFNγ-expressing memory CD4+ T cells in spleen following gp61-80 peptide restimulation and normalized to IFNγ background expression in naïve CD4+ T cells, there was a significantly higher frequency and number of IFNγ-expressing cells in the LCMV(1°) group ( Figs S1C-D ). The lack of IFNγ-expressing cells in the GP(1°) group was expected, as we previously reported that adjuvanted rGP immunization induces expansion of a CXCR5–IFNγ– nonpolarized T helper cell population in lieu of highly IFNγ-expressing Th1 cells as seen following LCMV infection (60). Together, these data show that both adjuvanted rGP immunization and LCMV infection induced I-A b :gp66-77 tetramer+ memory CD4+ Tfh and non-Tfh cells.…”

“…Regarding the importance of CD4+ T cells in formation of iBALT tertiary germinal center-like structures (116)(117)(118)(119)(120)(121), and that we saw increases in lung-resident Th1 and Tfh-like cells in heterologously primed mice, the differences in cellular composition or iBALT formation kinetics with either LCMV infection or adjuvanted rGP immunization priming compared to primary influenza infection warrants further investigation. As we have previously shown, non-Tfh cell populations are different between adjuvanted rGP immunization and LCMV infection (60), investigating the CD4+ T RM subsets resultant from these priming strategies and their distinct roles in their recall during an influenza challenge poses an interesting question, as IFN-secreting CD4+ T cells have been shown to be protective against influenza infection in secondary recalled responses (122,123).…”