Protein immunization induces T follicular helper memory cells and nonpolarized T helper (Tnp) memory cells

Abstract

Abstract Acute viral infection generates lineage-committed T helper 1 (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 T helper cells in vivo following protein vaccination is poorly understood. In this study, we analyzed effector and memory CD4+ T cell differentiation following adjuvanted glycoprotein immunization compared to acute lymphocytic choriomeningitis virus (LCMV) infection. Glycoprotein immunization-induced CXCR5-non-Tfh effector and memory CD4+ T cells that surprisingly had not undergone polarization toward any particular T helper cell lineage but had undergone memory differentiation. However, upon challenge with virus, these T helper 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.